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- Polverino, A; Coxon, A; Starnes, C; Diaz, Z; DeMelfi, T; Wang, L; Bready, J; Estrada, J; Cattley, R; Kaufman, S; Chen, D; Gan, Y; Kumar, G; Meyer, J; Neervannan, S; Alva, G; Talvenheimo, J; Montestruque, S; Tasker, A; Patel, V; Radinsky, R; Kendall, R AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66: 8715-21 (2006)
- Okaniwa, M; Imada, T; Ohashi, T; Miyazaki, T; Arita, T; Yabuki, M; Sumita, A; Tsutsumi, S; Higashikawa, K; Takagi, T; Kawamoto, T; Inui, Y; Yoshida, S; Ishikawa, T Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 2. Synthesis and characterization of a novel imide-type prodrug for improving oral absorption. Bioorg Med Chem 20: 4680-92 (2012)
- Samadi, A; Valderas, C; de los Ríos, C; Bastida, A; Chioua, M; González-Lafuente, L; Colmena, I; Gandía, L; Romero, A; Del Barrio, L; Martín-de-Saavedra, MD; López, MG; Villarroya, M; Marco-Contelles, J Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles. Bioorg Med Chem 19: 122-33 (2011)
- Kawakami, JK; Martinez, Y; Sasaki, B; Harris, M; Kurata, WE; Lau, AF Investigation of a novel molecular descriptor for the lead optimization of 4-aminoquinazolines as vascular endothelial growth factor receptor-2 inhibitors: application for quantitative structure-activity relationship analysis in lead optimization. Bioorg Med Chem Lett 21: 1371-5 (2011)
- Hirose, M; Okaniwa, M; Miyazaki, T; Imada, T; Ohashi, T; Tanaka, Y; Arita, T; Yabuki, M; Kawamoto, T; Tsutsumi, S; Sumita, A; Takagi, T; Sang, BC; Yano, J; Aertgeerts, K; Yoshida, S; Ishikawa, T Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives. Bioorg Med Chem 20: 5600-15 (2012)
- Gangjee, A; Kurup, S; Ihnat, MA; Thorpe, JE; Shenoy, SS Synthesis and biological activity of N(4)-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents. Bioorg Med Chem 18: 3575-87 (2010)
- Borzilleri, RM; Zheng, X; Qian, L; Ellis, C; Cai, ZW; Wautlet, BS; Mortillo, S; Jeyaseelan, R; Kukral, DW; Fura, A; Kamath, A; Vyas, V; Tokarski, JS; Barrish, JC; Hunt, JT; Lombardo, LJ; Fargnoli, J; Bhide, RS Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. J Med Chem 48: 3991-4008 (2005)
- Borzilleri, RM; Bhide, RS; Barrish, JC; D'Arienzo, CJ; Derbin, GM; Fargnoli, J; Hunt, JT; Jeyaseelan, R; Kamath, A; Kukral, DW; Marathe, P; Mortillo, S; Qian, L; Tokarski, JS; Wautlet, BS; Zheng, X; Lombardo, LJ Discovery and evaluation of N-cyclopropyl- 2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5- ylmethyl)amino)benzamide (BMS-605541), a selective and orally efficacious inhibitor of vascular endothelial growth factor receptor-2. J Med Chem 49: 3766-9 (2006)
- Huang, A; Moretto, A; Janz, K; Lowe, M; Bedard, PW; Tam, S; Di, L; Clerin, V; Sushkova, N; Tchernychev, B; Tsao, DH; Keith, JC; Shaw, GD; Schaub, RG; Wang, Q; Kaila, N Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury. J Med Chem 53: 6003-17 (2010)
- Samadi, A; Marco-Contelles, J; Soriano, E; Alvarez-Pérez, M; Chioua, M; Romero, A; González-Lafuente, L; Gandía, L; Roda, JM; López, MG; Villarroya, M; García, AG; Ríos, Cde L Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles. Bioorg Med Chem 18: 5861-72 (2010)
- Sun, L; Liang, C; Shirazian, S; Zhou, Y; Miller, T; Cui, J; Fukuda, JY; Chu, JY; Nematalla, A; Wang, X; Chen, H; Sistla, A; Luu, TC; Tang, F; Wei, J; Tang, C Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46: 1116-9 (2003)
- Thompson, AM; Delaney, AM; Hamby, JM; Schroeder, MC; Spoon, TA; Crean, SM; Showalter, HD; Denny, WA Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases. J Med Chem 48: 4628-53 (2005)
- Gingrich, DE; Reddy, DR; Iqbal, MA; Singh, J; Aimone, LD; Angeles, TS; Albom, M; Yang, S; Ator, MA; Meyer, SL; Robinson, C; Ruggeri, BA; Dionne, CA; Vaught, JL; Mallamo, JP; Hudkins, RL A new class of potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the identification of CEP-5214 and its dimethylglycine ester prodrug clin J Med Chem 46: 5375-88 (2003)
- Hudkins, RL; Becknell, NC; Zulli, AL; Underiner, TL; Angeles, TS; Aimone, LD; Albom, MS; Chang, H; Miknyoczki, SJ; Hunter, K; Jones-Bolin, S; Zhao, H; Bacon, ER; Mallamo, JP; Ator, MA; Ruggeri, BA Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c J Med Chem 55: 903-13 (2012)
- Cai, ZW; Zhang, Y; Borzilleri, RM; Qian, L; Barbosa, S; Wei, D; Zheng, X; Wu, L; Fan, J; Shi, Z; Wautlet, BS; Mortillo, S; Jeyaseelan, R; Kukral, DW; Kamath, A; Marathe, P; D'Arienzo, C; Derbin, G; Barrish, JC; Robl, JA; Hunt, JT; Lombardo, LJ; Fargnoli, J; Bhide, RS Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215 J Med Chem 51: 1976-80 (2008)
- ChEBML_213951 Inhibitory activity against Vascular endothelial growth factor receptor
- ChEBML_213959 Inhibition of vascular endothelial growth factor receptor 1
- ChEBML_213960 Inhibition of Vascular endothelial growth factor receptor 1
- ChEBML_213967 Inhibition of Vascular endothelial growth factor receptor 2
- ChEBML_213970 Inhibition of Vascular endothelial growth factor receptor 2
- ChEBML_214231 Inhibition of Vascular endothelial growth factor receptor 2
- ChEBML_214243 Inhibition of Vascular endothelial growth factor receptor 2
- ChEBML_214253 Inhibition of Vascular endothelial growth factor receptor 3
- ChEMBL_213950 (CHEMBL811928) Inhibition of Vascular endothelial growth factor receptor
- ChEMBL_306570 (CHEMBL832087) Inhibition of Vascular endothelial growth factor receptor
- ChEBML_214094 Inhibition of human vascular endothelial growth factor receptor 2
- ChEBML_214117 Inhibitory activity against Vascular endothelial growth factor receptor 2
- ChEMBL_213947 (CHEMBL811925) Inhibition of Vascular endothelial growth factor receptor 3
- ChEMBL_213951 (CHEMBL811929) Inhibitory activity against Vascular endothelial growth factor receptor
- ChEMBL_213964 (CHEMBL811941) Inhibition of Vascular endothelial growth factor receptor 1
- ChEMBL_214113 (CHEMBL820699) Inhibition of Vascular endothelial growth factor receptor 2
- ChEMBL_214115 (CHEMBL820701) Inhibition of Vascular endothelial growth factor receptor 2
- ChEMBL_214240 (CHEMBL819558) Inhibition of Vascular endothelial growth factor receptor 2
- ChEMBL_214243 (CHEMBL820211) Inhibition of Vascular endothelial growth factor receptor 2
- ChEMBL_214250 (CHEMBL820849) Inhibition of Vascular endothelial growth factor receptor 3
- ChEMBL_305183 (CHEMBL876146) Inhibition of vascular endothelial growth factor receptor 2
- ChEMBL_305535 (CHEMBL828555) Inhibition of vascular endothelial growth factor receptor 2
- ChEMBL_877987 (CHEMBL2189053) Inhibition of vascular endothelial growth factor receptor 2
- ChEBML_213807 Ability to inhibit expression of Vascular cell adhesion molecule 1
- ChEMBL_214107 (CHEMBL820693) Inhibition of human Vascular endothelial growth factor receptor 2
- ChEMBL_305511 (CHEMBL831112) inhibitory activity against Vascular endothelial growth factor receptor 2
- ChEMBL_305679 (CHEMBL828051) Inhibition of human Vascular endothelial growth factor receptor 2
- ChEMBL_306103 (CHEMBL830878) Inhibitory concentration against Vascular endothelial growth factor receptor 2
- ChEMBL_65317 (CHEMBL678090) Inhibitory activity against human vascular endothelial nitric oxide synthase.
- ChEBML_213820 Inhibition of TNF-alpha inducible Vascular cell adhesion molecule-1 expression.
- ChEMBL_213948 (CHEMBL811926) Inhibitory activity against vascular endothelial growth factor receptor 2 (FLK1)
- ChEMBL_213949 (CHEMBL811927) Inhibitory activity against vascular endothelial growth factor receptor 2 (FLK1)
- ChEMBL_214241 (CHEMBL819559) Inhibition of Vascular endothelial growth factor receptor 2 (VEGFR-2)
- ChEMBL_305774 (CHEMBL827963) In vitro inhibition of Vascular endothelial growth factor receptor 2
- ChEMBL_321426 (CHEMBL881957) Inhibitory concentration against human Vascular endothelial growth factor receptor 2
- ChEBML_214091 Inhibition of Vascular endothelial growth factor receptor 2 at 5 uM ATP
- ChEBML_214114 Inhibition of vascular endothelial growth factor receptor 2 autophosphorylation in intact cells
- ChEMBL_213973 (CHEMBL812622) Inhibition of Vascular endothelial growth factor receptor 2 (VEGFR-2) autophosphorylation
- ChEMBL_305591 (CHEMBL828038) Inhibition of human vascular endothelial growth factor receptor 2 (Flk-1)
- ChEMBL_305649 (CHEMBL829507) Inhibition of human vascular endothelial growth factor receptor 2 (VEGFR-2)
- ChEMBL_305849 (CHEMBL829589) Inhibition of human vascular endothelial growth factor receptor 2 kinase activity
- ChEMBL_213976 (CHEMBL820672) In vitro inhibition of Vascular endothelial growth factor receptor 2 (VEGFR-2)
- ChEMBL_213978 (CHEMBL817492) In vitro inhibitory concentration against human vascular endothelial growth factor receptor 2
- ChEMBL_305757 (CHEMBL829528) Inhibition of vascular endothelial growth factor receptor 2 in cell-free assay
- ChEMBL_305820 (CHEMBL829563) Inhibition of vascular endothelial growth factor receptor 2 in cell-intact assay
- ChEMBL_306571 (CHEMBL832088) Inhibition of Vascular endothelial growth factor receptor 2(KDR) without DTT (dithiothreitol)
- ChEMBL_306585 (CHEMBL832932) Inhibition of Vascular endothelial growth factor receptor 2(KDR) with DTT (dithiothreitol)
- ChEMBL_63185 (CHEMBL677396) Binding affinity against endothelin A receptor from rabbit renal vascular smooth muscles
- ChEMBL_64033 (CHEMBL671552) Binding affinity against endothelin B receptor from rabbit renal vascular smooth muscles
- ChEBML_65825 Effective concentration against ET A receptor from rabbit renal artery vascular smooth muscle cells
- ChEMBL_217453 (CHEMBL823502) Inhibitory activity against alpha4-beta1 integrin (vascular cell adhesion molecule) in ELISA assay
- ChEMBL_65826 (CHEMBL877809) Ability to inhibit [125I]ET1 binding to vascular smooth muscle (vsm)- A10 cells
- ChEBML_217441 Inhibition of VCAM (vascular cell adhesion molecule) adhesion to alpha4-beta1 integrin of leukocyte cells
- ChEMBL_213408 (CHEMBL878745) Inhibition of Very late antigen 4/vascular cell adhesion molecule 1 interaction in ELISA
- ChEMBL_306228 (CHEMBL831136) In vitro inhibition of Vascular endothelial growth factor receptor 2 at 10 uM ATP
- ChEMBL_313055 (CHEMBL835746) Inhibition of vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cell proliferation
- ChEMBL_321627 (CHEMBL871636) Inhibition of Vascular endothelial growth factor receptor 2 kinase phosphorylation of pGAT-biotin peptide
- ChEMBL_63188 (CHEMBL679791) Antagonistic activity against endothelin A receptor in rabbit renal artery vascular smooth muscle cells.
- ChEMBL_63196 (CHEMBL679799) Inhibition of binding to Endothelin A receptor of rabbit renal vascular smooth muscle cells
- ChEMBL_65825 (CHEMBL682959) Effective concentration against ET A receptor from rabbit renal artery vascular smooth muscle cells
- ChEMBL_65829 (CHEMBL682962) Binding affinity against ET A receptor from rabbit renal artery vascular smooth muscle cells
- ChEMBL_92772 (CHEMBL700072) Inhibition of L-type [Ca2+] channel (VSCC) in rat A7r5 vascular smooth muscle cells
- ChEMBL_1622 (CHEMBL616647) Tested for 5-hydroxytryptamine 1D like receptor-mediated vascular effect in rabbit saphenous vein (RSV)
- ChEMBL_213957 (CHEMBL811935) In vitro inhibition of Vascular endothelial growth factor receptor 1 (VEGFR-1) expressed in baculovirus
- ChEMBL_213958 (CHEMBL811936) In vitro inhibition of Vascular endothelial growth factor receptor 1 (VEGFR-1) expressed in baculovirus
- ChEMBL_213975 (CHEMBL812788) In vitro inhibition of Vascular endothelial growth factor receptor 2 (VEGFR-2) expressed in baculovirus
- ChEMBL_217305 (CHEMBL823926) Inhibition of alpha4-beta1 interaction to vascular cell adhesion molecule-1 (VCAM-1) was determined
- ChEMBL_329316 (CHEMBL863412) Activity against 5HT2A mediated intracellular calcium mobilization by FLIPR in rat vascular smooth muscle cells
- ChEMBL_63193 (CHEMBL679796) Inhibition of ET-1 stimulated arachidonic acid release in rabbit renal vascular smooth muscle cells
- ChEBML_214087 Inhibition of vascular endothelial growth factor receptor 2 activity with 1 mM ATP and biotinylated lck peptide
- ChEBML_214092 Inhibitory activity against vascular endothelial growth factor receptor 2 (VEGFR2) at a concentration of 5 uM ATP.
- ChEBML_63191 Displacement of [125I]-ET-1 from Endothelin A receptor of rabbit renal artery vascular smooth muscle cells
- ChEMBL_213547 (CHEMBL816251) Inhibition of Very late antigen 4 of Ramos cell adhesion to vascular cell adhesion molecule 1
- ChEMBL_217312 (CHEMBL824471) Inhibition of very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1(VCAM -1) interaction
- ChEMBL_65830 (CHEMBL682963) Binding affinity against Endothelin A receptor in rabbit renal artery vascular smooth muscle membrane (ET-A)
- ChEBML_63192 Inhibition of ET-1 binding to Endothelin A receptor in cultured rabbit renal artery vascular smooth muscle cells
- ChEMBL_1621 (CHEMBL616646) Compound was tested for 5-hydroxytryptamine 1D like receptor-mediated vascular effect in rabbit saphenous vein (RSV)
- ChEMBL_1880 (CHEMBL616477) Compound was tested for 5-hydroxytryptamine 1D like receptor-mediated vascular effect in rabbit saphenous vein (RSV)
- ChEMBL_214249 (CHEMBL820848) In vitro inhibition of Vascular endothelial growth factor receptor 3 [VEGFR-3(Flt-4)] expressed in baculovirus
- ChEMBL_63191 (CHEMBL679794) Displacement of [125I]-ET-1 from Endothelin A receptor of rabbit renal artery vascular smooth muscle cells
- ChEMBL_63197 (CHEMBL873588) Tested for antagonistic activity against Endothelin A receptor in the rabbit renal artery vascular smooth muscle cells.
- ChEBML_1682364 Inhibition of MAGL in human brain vascular pericytes after 1 hr by TAMRA azide-based In-gel fluorescence method
- ChEMBL_213979 (CHEMBL817493) Inhibition of VEGFR induced autophosphorylation of human Vascular endothelial growth factor receptor 2 (VEGFR2) transfected in CHO cells
- ChEMBL_2565 (CHEMBL617112) In vitro relative agonist activity against 5-hydroxytryptamine 2A using PI assay in rat vascular smooth muscle cells
- ChEMBL_1682364 (CHEMBL4032641) Inhibition of MAGL in human brain vascular pericytes after 1 hr by TAMRA azide-based In-gel fluorescence method
- ChEMBL_63187 (CHEMBL679790) Compound was evaluated for the receptor binding activity in rabbit artery vascular smooth muscle cells expressing Endothelin A receptor
- ChEMBL_63217 (CHEMBL674069) Antagonism of [125 I]ET-1 binding to the rat endothelin receptor in vascular smooth muscle VSM-A10 cells.
- ChEMBL_2372413 Antagonist activity at alpha4beta1 integrin receptor in human Jurkat E6.1 cells assessed as inhibition of vascular cell adhesion molecule 1-induced cell adhesion pre-incubated for 30 mins followed by 30 mins incubation in vascular cell adhesion molecule 1 coated wells by fluorescence plate reader assay
- ChEMBL_2372414 Agonist activity at alpha4beta1 integrin receptor in human Jurkat E6.1 cells assessed as inhibition of vascular cell adhesion molecule 1-induced cell adhesion pre-incubated for 30 mins followed by 30 mins incubation in vascular cell adhesion molecule 1 coated wells by fluorescence plate reader assay
- ChEBML_63195 Inhibition of [125I]endothelin-1 [ET-1] binding to endothelin A receptor (ETA) of rabbit renal artery vascular smooth muscle cells
- ChEMBL_199704 (CHEMBL803587) In vitro potency against TNF alpha induced expression of Selectin E on human vascular endothelial cells using CAM ELISA assay
- ChEMBL_213542 (CHEMBL816989) Inhibition of Very late antigen 4 (VLA-4) of Ramos cell adhesion to vascular cell adhesion molecule 1 (VCAM-1)
- ChEMBL_213544 (CHEMBL816991) Inhibition of binding of Very late antigen 4/vascular cell adhesion molecule 1 in a protein-based ligand binding assay
- ChEMBL_213817 (CHEMBL815900) In vitro potency against TNF alpha induced expression of VCAM-1 on human vascular endothelial cells using CAM ELISA assay
- ChEMBL_63194 (CHEMBL679797) Inhibition of Endothelin A receptor mediated (ET-1) release of arachidonic acid from rabbit renal artery vascular smooth muscle cells
- ChEBML_225759 Inhibition of ET- 1 stimulated arachidonic acid release (AAR) in cultured rabbit renal vascular smooth muscle cells expressing the endothelin A receptor.
- ChEBML_63190 Compound was tested for its ability to inhibit Endothelin A receptor induced arachidonic acid release(AARA) in rabbit renal artery vascular smooth muscles.
- ChEMBL_213543 (CHEMBL816990) Inhibition of binding of Very late antigen 4/vascular cell adhesion molecule 1 in a cell based ligand binding assay (Jurkat cells)
- ChEMBL_217611 (CHEMBL819426) Inhibition of alpha4-beta7 integrin binding to radiolabeled vascular cell adhesion molecule-1 (VCAM-1) Ig fusion protein in human Jurkat cells
- ChEMBL_225759 (CHEMBL848083) Inhibition of ET- 1 stimulated arachidonic acid release (AAR) in cultured rabbit renal vascular smooth muscle cells expressing the endothelin A receptor.
- ChEMBL_225760 (CHEMBL848084) Inhibition of ET- 1 stimulated arachidonic acid release (AAR) in cultured rabbit renal vascular smooth muscle cells expressing the endothelin B receptor.
- ChEMBL_2372423 Antagonist activity at alpha4beta1 integrin receptor in human Jurkat E6.1 cells assessed as inhibition of vascular cell adhesion molecule 1-induced cell adhesion
- ChEMBL_89064 (CHEMBL697203) In vitro potency against TNF alpha induced expression of intercellular adhesion molecule-1 on human vascular endothelial cells using CAM ELISA assay
- ChEMBL_2372415 Antagonist activity at alpha4beta7 integrin receptor in human RPMI-8866 cells assessed as inhibition of mucosal vascular add-ressin cell adhesion molecule 1-induced cell adhesion pre-incubated for 30 mins followed by 30 mins incubation in mucosal vascular add-ressin cell adhesion molecule 1 coated wells by fluorescence plate reader assay
- ChEMBL_2372416 Agonist activity at alpha4beta7 integrin receptor in human RPMI-8866 cells assessed as inhibition of mucosal vascular add-ressin cell adhesion molecule 1-induced cell adhesion pre-incubated for 30 mins followed by 30 mins incubation in mucosal vascular add-ressin cell adhesion molecule 1 coated wells by fluorescence plate reader assay
- ChEMBL_63190 (CHEMBL679793) Compound was tested for its ability to inhibit Endothelin A receptor induced arachidonic acid release(AARA) in rabbit renal artery vascular smooth muscles.
- ChEMBL_1566203 (CHEMBL3788344) Displacement of [125I]-Ang II from Angiotensin 2 type-1A receptor in rat vascular smooth muscle cells after 150 mins by gamma counting method
- ChEMBL_64015 (CHEMBL671536) Ability to block endothelin-1 (ET-1) stimulated arachidonic acid release in rabbit renal vascular smooth muscle cells (AARA) expressing recombinant rat endothelin B (ETB) receptor
- ChEMBL_306909 (CHEMBL828352) Inhibition of Very late antigen-4 (VLA-4) expressing human leukemia cells (HL-60) aggregation with human Vascular cell adhesion molecule-1 (VCAM-1) expressing chinese hamster ovary (CHO) cells
- ChEMBL_2372426 Binding affinity to alpha4beta1 integrin receptor (unknown origin) preincubated for 30 mins followed by 30 mins incubation in vascular cell adhesion molecule 1-induced cell adhesion coated wells by fluorescence based assay
- ChEMBL_2372427 Binding affinity to alpha4beta7 integrin receptor (unknown origin) preincubated for 30 mins followed by 30 mins incubation in mucosal vascular add-ressin cell adhesion molecule 1 coated wells by fluorescence based assay
- In Vitro Activity Assay In Vitro Activity: Evaluation of NMDAR Blocking Activity Using Patch-ClampPrevious studies have shown that the NMDAR exists in the peripheral vasculature.All NMDAR subunits were examined by RT-PCR and sequencing in the peripheral endothelium and peripheral vascular smooth muscle cells. The sequences of these NMDAR subunits in both vascular cells showed a high similarity if not identity to the sequences of brain NMDAR (Chen H et al, J Vasc Surg 2005, Qureshi I et al Vasc Med 2005).The molecules described herein were tested in serial concentrations ranging from 1 nM to 100 μM for their NMDAR blocking activity using patch-clamp.
- Binding Assay A competition binding assay (DiscoveRx KINOMEscan) was used to measure the ability of the compound to compete for binding of an immobilized adenosine triphosphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. The ability of the test compound to compete with the immobilized ligand was measured using quantitative polymerase chain reaction (qPCR) of the DNA tag.
- sEH_DR_Inh_Infinite200_Fluorescence_01072008 Data Source: Columbia University Molecular Screening Center Source (MLSCN Center Name): Columbia University Molecular Screening Center Center Affiliation: Columbia University Molecular Screening Center Assay Provider: Dr. Bruce D. Hammock, UC, Davis, CA. Network: Molecular Library Screening Center Network (MLSCN) Grant Proposal Number: X01 MH078954-01 Hypertension and vascular inflammation are associated with cardiovascular diseases, the primary cause of death in our society. Because a large proportion of patients are not responding to current therapies, the next generation of drugs will not only need to reduce blood pressure but also treat vascular and renal inflammation as well as reduce smooth muscle cell proliferation, which in turn should also reduce hypertension related organ damage. Using inhibitors developed in the Hammock laboratory, it was shown that the inhibition of soluble epoxide hydrolase (sEH) has therapeutic application in the treatment of hypertension and several in
- Dose-response biochemical assay for antagonists of the interaction between the Eph receptor B4 (EphB4) and its ligand ephrin-B2 via TNYL-RAW peptide Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute, TSRI Assay Provider: Peter Kuhn, TSRI Network: Molecular Library Screening Center Network (MLSCN) Grant Proposal Number: 1 X01 MH079857-01 Grant Proposal PI: Peter Kuhn External Assay ID: EphB4TNYLRAW_INH_FP_1536_IC50 Name: Dose-response biochemical assay for antagonists of the interaction between the Eph receptor B4 (EphB4) and its ligand ephrin-B2 via TNYL-RAW peptide Description: The erythropoietin-producing hepatocellular (Eph) receptor family is the largest family of receptor tyrosine kinases identified to date, with 16 structurally similar family members(1). The Eph family plays important roles in both the developing and adult tissues, and is involved in biological processes such as tissue patterning, vascular system development, axonal guidance, and neuronal development (2-4). During vascular development, the Eph receptor B4 (EphB4) is p
- TSP1 inhibitory activity As referred to herein, the TSP1 inhibitory activity refers to the activity to inhibit one or more effects of TSP1, including angiostatic effect. The TSP1 inhibitory activity is measured by a cell adhesion inhibition assay using human TSP1 and vascular endothelial cells as described hereinbelow in the Examples section. In this assay, when the 50% inhibitory concentration (IC5O) of a test substance is 200 nM or less, the test substance is determined to have TSP1 inhibitory activity.
- Inhibitory Activity Assay Factor IX is a key component of the plasma system that forms a fibrin clot at a site of vascular injury. The activity of Factor IXa is measured by monitoring the cleavage of the fluorescent peptide, CH3SO2-D-CHG-Gly-Arg-AFC.AcOH ( CHG is cyclohexyl-glycine and AFC is trifluoro aminomethyl coumarin). Factor IXa cleaves the amide bond between Arg and AFC, thereby releasing the AFC fluorophore. The free AFC can be detected with a fluorescence detector at an excitation wavelength of 405 nM and emission wavelength of 510 nM.
- In vitro kinase inhibition assay An in vitro kinase assay was performed to evaluate the kinase suppression activity of the most promising cytotoxic candidates 4b, 4j against four different receptor tyrosine kinases (RTKs) - namely epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER2), vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR). The activities of the examined compounds against EGFR, HER2, PDGFR-β, and VEGFR2 were in vitro tested using Abcam's Human In cell ELISA Kit (ab 126419) for EGFR, ADP-Glo TM Kinase Assay for Her2, PDGFR-β, active, recombinant protein expressed in Sf9 cells for VEGFR2 (KDR) Kinase Assay Kit Catalog No. 40325, respectively.
- Determination of Inhibitory Activity Against Factor IXa Formation of a clot to stem bleeding at a site of blood vessel injury involves the coordinated activity of a group of plasma proteins that initiate and propagate fibrin formation and subsequently protect fibrin from premature degradation. Factor IX is a key component of the plasma system that forms a fibrin clot at a site of vascular injury. The activity of Factor IXa is measured by monitoring the cleavage of the fluorescent peptide, CH3SO2-D-CHG-Gly-Arg-AFC.AcOH (CHG is cyclohexyl-glycine and AFC is trifluoro aminomethyl coumarin). Factor IXa cleaves the amide bond between Arg and AFC, thereby releasing the AFC fluorophore. The free AFC can be detected with a fluorescence detector at an excitation wavelength of 405 nM and emission wavelength of 510 nM.
- Counterscreen for S1P2 Antagonists: Dose Response Cell-Based Screen to Identify Antagonists of CRE-BLA Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Network: Molecular Library Screening Center Network (MLSCN) Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: CRE _ANT_BLA_384_IC50_Counterscreen_ S1P2_Hits Name: Counterscreen for S1P2 Antagonists: Dose Response Cell-Based Screen to Identify Antagonists of CRE-BLA Description: Sphingosine 1-phosphate (S1P) influences heart rate [1,2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2,4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2)
- Dose Response Cell Based Assay for Antagonists of the S1P2 Receptor Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Network: Molecular Library Screening Center Network (MLSCN) Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: S1P2_ANT_BLA_384_IC50 Name: Dose Response Cell Based Assay for Antagonists of the S1P2 Receptor Description: Sphingosine 1-phosphate (S1P) influences heart rate [1,2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2,4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2), also known as endothelial differentiation sphingolipid G-pro
- Estrogen Receptor (alpha) binding: Dose Response of Primary Screen Assay University of New Mexico Assay Overview: Assay Support: 1X01 MH077627-01 Assay for Ligands of GPR30 and Classical Estrogen Receptors PI: Eric Prossnitz, PhD Assay Development: Megan Dennis Assay Implementation: Megan Dennis, Mark Haynes, PhD Target Team Leader for the Center: Eric Prossnitz, PhD (EProssnitz@salud.unm.edu) Assay Background and Significance: The physiological effects of estrogen are diverse and numerous, with roles in growth, development and homeostasis of numerous tissues. Roles for estrogen in mammalian female reproductive development are among the best defined, but estrogen also plays a part in regulation of skeletal cancer, (cardio)vascular function, the central nervous system as well as in the immune system. Stimulation with estrogen induces many signaling pathways, leading to an array of cellular responses including adhesion, migration, survival, proliferation and angiogenesis in both normal and neoplastic tissues [Edwards et al., 2005]. Effects of estrogen
- Estrogen Receptor (beta) binding: Dose Response of Primary Screen Assay University of New Mexico Assay Overview: Assay Support: 1X01 MH077627-01 Assay for Ligands of GPR30 and Classical Estrogen Receptors PI: Eric Prossnitz, PhD Assay Development: Megan Dennis Assay Implementation: Megan Dennis, Mark Haynes, PhD Target Team Leader for the Center: Eric Prossnitz, PhD (EProssnitz@salud.unm.edu) Assay Background and Significance: The physiological effects of estrogen are diverse and numerous, with roles in growth, development and homeostasis of numerous tissues. Roles for estrogen in mammalian female reproductive development are among the best defined, but estrogen also plays a part in regulation of skeletal cancer, (cardio)vascular function, the central nervous system as well as in the immune system. Stimulation with estrogen induces many signaling pathways, leading to an array of cellular responses including adhesion, migration, survival, proliferation and angiogenesis in both normal and neoplastic tissues [Edwards et al., 2005]. Effects of estrogen
- Counter screen for S1P2 Agonists: Dose Response High Throughput Cell-Based Screen to Identify Activators of CRE-BLA Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: Counterscreen for S1P2 Agonists: Dose Response High Throughput Cell-Based Screen to Identify Activators of CRE-BLA Name: CRE_AG_BLA_384_EC50_%ACT Description: Sphingosine 1-phosphate (S1P) influences heart rate [1,2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2,4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2), also known as endothelial differentiation sphingolipid G-protein-coup
- Counterscreen for S1P2 Agonists: Dose Response High Throughput Cell-Based Screen to Identify Activators of CRE-BLA: S1P2 Purchased Analogues Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: CRE_AG_BLA_384_EC50_S1P2_Purchased_Analogues Name: Counterscreen for S1P2 Agonists: Dose Response High Throughput Cell-Based Screen to Identify Activators of CRE-BLA: S1P2 Purchased Analogues Description: Sphingosine 1-phosphate (S1P) influences heart rate [1,2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2,4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2), also known as endothelial
- Dose Response Cell Based Assay for Agonists of the S1P2 Receptor Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: S1P2_AG_BLA_384_EC50 Name: Dose Response Cell Based Assay for Agonists of the S1P2 Receptor Description: Sphingosine 1-phosphate (S1P) influences heart rate [1, 2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2, 4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2), also known as endothelial differentiation sphingolipid G-protein-coupled receptor 5 (EDG5), signals through Gi, Gq and G1
- Dose Response Cell Based Assay for Agonists of the S1P2 Receptor of Purchased Analogues Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute (TSRI) Assay Provider: Hugh Rosen, TSRI Grant Proposal Number: 1 R03 MH076533-01 Grant Proposal PI: Germana Sanna External Assay ID: S1P2_AG_BLA_384_EC50_Purchased_Analogues Name: Dose Response Cell Based Assay for Agonists of the S1P2 Receptor of Purchased Analogues Description: Sphingosine 1-phosphate (S1P) influences heart rate [1, 2], coronary artery caliber, endothelial integrity, lung epithelial integrity [3] and lymphocyte recirculation [2, 4] through five related high affinity G-protein coupled receptors [5]. Subtype-selective modulators of S1P receptors will be of broad utility in understanding cell functions in vitro and vascular physiology in vivo, as well as de-convoluting the role of individual subtypes in cellular processes. The S1P receptor 2 (S1P2), also known as endothelial differentiation sphingolipid G-protein-coupled recepto
- VEGF-R2 Binding Assay A competition binding assay (DiscoveRx KINOMEscan) was used to measure the ability of the compound to compete for binding of an immobilized adenosine triphosphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. The ability of the test compound to compete with the immobilized ligand was measured using quantitative polymerase chain reaction (qPCR) of the DNA tag (Fabian, et al, Nature Biotechnology (2005) 23, 329-336; Karaman, et al, Nature Biotechnology (2008) 26, 127-132).A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E. coli) derived from the BL21 strain. The E. coli were grown to log-phase, infected with VEGFR2 tagged T7 phage and then incubated with shaking at 32 ° C. until lysis. The lysate containing the kinase was then centrifuged and filtered to remove cell debris. Affinity resin for the VEGFR2 assay was prepared by treating Streptavidin-coated magnetic beads with a biotinylated small molecule.
- VEGFR2 and RET9 Binding Assay A competition binding assay, was used to measure the ability of a compound to compete for binding of an immobilized adenosine triphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E. coli) derived from the BL21 strain. The E. coli were grown to log-phase, infected with VEGFR2 tagged T7 phage and then incubated with shaking at 32° C. until lysis. The lysate containing the kinase was then centrifuged and filtered to remove cell debris. Affinity resin for the VEGFR2 assay was prepared by treating Streptavidin-coated magnetic beads with a biotinylated small molecule ligand for 30 minutes at room temperature. The beads were blocked with excess biotin and then washed with blocking buffer (SEABLOCK (PIERCE), 1% bovine serum albumin, 0.17% phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol). The binding reaction was initiated by combining in a well of a polystyrene 96-well plate, DNA tagged VEGFR2, liganded affinity beads and the serial diluted test compound in 1× binding buffer (20% SEABLOCK, 0.17× phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol) in a final volume of 0.135 ml. The assay plates were incubated at room temperature with shaking for 1 hour and then the beads were washed with wash buffer (1× phosphate buffered saline, 0.05% TWEEN 20).
- Binding Assay A competition binding assay was used to measure the ability of a compound to compete for binding of an immobilized adenosine triphosphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. The ability of the test compound to compete with the immobilized ligand was measured using quantitative polymerase chain reaction (qPCR) of the DNA tag. A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E. coli) derived from the BL21 strain. The E. coli were grown to log-phase, infected with VEGFR2 tagged T7 phage and then incubated with shaking at 32° C. until lysis. The lysate containing the kinase was then centrifuged and filtered to remove cell debris. Affinity resin for the VEGFR2 assay was prepared by treating Streptavidin-coated magnetic beads with a biotinylated small molecule ligand for 30 minutes at room temperature. The beads were blocked with excess biotin and then washed with blocking buffer SEABLOCK(PIERCE), 1% bovine serum albumin, 0.17% phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol). The binding reaction was initiated by combining in a well of a polystyrene 96-well plate, DNA tagged VEGFR2, liganded affinity beads and the serial diluted test compound in 1× binding buffer (20% SEABLOCK, 0.17× phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol) in a final volume of 0.135 ml. The assay plates were incubated at room temperature with shaking for 1 hour and then the beads were washed with wash buffer (1× phosphate buffered saline, 0.05% TWEEN 20). The beads were re-suspended in elution buffer (1× phosphate buffered saline, 0.05% TWEEN 20, 0.05 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The VEGFR2 concentration in the eluate was measured using qPCR.
- Fluorometric Assay The capability of compounds described herein to inhibit the enzymatic activity of vascular adhesion protein-1 (VAP-1) was determined by fluorometric assay. The assay procedure provided by R&D Systems was modified slightly for use as an inhibitor screening assay. The assay measured the H2O2 generated from the oxidative deamination of benzylamine by rhVAP-1 by converting Amplex Red to the fluorescent product, resorufin, via horseradish peroxidase (HRP) and H2O2. Reaction buffer was 10 mM NaHCO3, pH 7.4. A standard curve was prepared by serially diluting H2O2 in reaction buffer. A 10 μM solution of resorufin was prepared in reaction buffer and was dispensed to 2 wells. These wells served as positive control for maximum fluorescence. Reaction buffer was added to the individual wells so that the final volume in each well was 100 μL. Amplex Red was diluted to 1 mM in reaction buffer. A 10 U stock of HRP was prepared in reaction buffer. A reaction cocktail was prepared by mixing equal parts 1 mM Amplex Red with 10 U HRP with 3 parts reaction buffers. The reaction cocktail was added to the appropriate wells, so that that final concentration in the well was 0.05 mM Amplex Red and 0.5 U HRP. A 200 μM solution of benzylamine was prepared in reaction buffer. Benzylamine was added to the appropriate wells so that the final concentration was 50 μM. Inhibitors were diluted in DMSO to 20 and distributed to the appropriate wells. UP-1207 served a positive control. rhVAP-1 was purchased from R&D Systems. The concentration used for each lot was determined so that the activity was equal to the first lot. Two wells were left blank as controls. The plate was incubated for 30 minutes at 37 C., protected from light under foil. The plate was read at 530/35 emission and 590/35 excitation. Data processing was performed using Excel and Prism software.
- VAP-1 Assay The capability of compounds described herein to inhibit the enzymatic activity of vascular adhesion protein-1 (VAP-1) was determined by fluorometric assay. The assay procedure provided by R&D Systems was modified slightly for use as an inhibitor screening assay. The assay measured the H2O2 generated from the oxidative deamination of benzylamine by rhVAP-1 by converting Amplex Red to the fluorescent product, resorufin, via horseradish peroxidase (HRP) and H2O2. Reaction buffer was 10 mM NaHCO3, pH 7.4. A standard curve was prepared by serially diluting H2O2 in reaction buffer. A 10 μM solution of resorufin was prepared in reaction buffer and was dispensed to 2 wells. These wells served as positive control for maximum fluorescence. Reaction buffer was added to the individual wells so that the final volume in each well was 100 μL. Amplex Red was diluted to 1 mM in reaction buffer. A 10 U stock of HRP was prepared in reaction buffer. A reaction cocktail was prepared by mixing equal parts 1 mM Amplex Red with 10 U HRP with 3 parts reaction buffers. The reaction cocktail was added to the appropriate wells, so that that final concentration in the well was 0.05 mM Amplex Red and 0.5 U HRP. A 200 μM solution of benzylamine was prepared in reaction buffer. Benzylamine was added to the appropriate wells so that the final concentration was 50 μM. Inhibitors were diluted in DMSO to 20 and distributed to the appropriate wells. LJP-1207 served a positive control. rhVAP-1 was purchased from R&D Systems. The concentration used for each lot was determined so that the activity was equal to the first lot. Two wells were left blank as controls. The plate was incubated for 30 minutes at 37 C., protected from light under foil. The plate was read at 530/35 emission and 590/35 excitation. Data processing was performed using Excel and Prism software.
- VEGF-R2 Binding Assay A competition binding assay (DiscoveRx KINOMEscan ) was used to measure the ability of the compound to compete for binding of an immobilized adenosine triphosphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. The ability of the test compound to compete with the immobilized ligand was measured using quantitative polymerase chain reaction (qPCR) of the DNA tag (Fabian, et al, Nature Biotechnology (2005) 23, 329-336; Karaman, et al, Nature Biotechnology (2008) 26, 127-132).A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E. coli) derived from the BL21 strain. The E. coli were grown to log-phase, infected with VEGFR2 tagged T7 phage and then incubated with shaking at 32° C. until lysis. The lysate containing the kinase was then centrifuged and filtered to remove cell debris. Affinity resin for the VEGFR2 assay was prepared by treating Streptavidin-coated magnetic beads with a biotinylated small molecule ligand for 30 minutes at room temperature. The beads were blocked with excess biotin and then washed with blocking buffer (SeaBlock (Pierce), 1% bovine serum albumin, 0.17% phosphate buffered saline, 0.05% Tween 20, 6 mM dithiothreitol). The binding reaction was initiated by combining in a well of a polystyrene 96-well plate, DNA tagged VEGFR2, liganded affinity beads and the serial diluted test compound in 1× binding buffer (20% SeaBlock, 0.17× phosphate buffered saline, 0.05% Tween 20, 6 mM dithiothreitol) in a final volume of 0.135 ml. The assay plates were incubated at room temperature with shaking for 1 hour and then the beads were washed with wash buffer (1× phosphate buffered saline, 0.05% Tween 20). The beads were re-suspended in elution buffer (1× phosphate buffered saline, 0.05% Tween 20, 0.05 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The VEGFR2 concentration in the eluate was measured using qPCR.An 11-point dose response curve of 3-fold serial diluted test compound starting at 1 μM was used to determine the VEGFR2 binding constant (Kd). The compounds were prepared in 100% DMSO at 100× the final test concentration and then diluted to 1× in the assay for final DMSO concentration of 1%. Binding constants were calculated with standard dose-response curve using the Hill equation with Hill slope set to −1. Curves were fit using a non-linear least square fit with the Levenberg-Marquardt algorithm.
- VEGFR2 Binding Assay A competition binding assay (DISCOVERX KINOMESCAN ) was used to measure the ability of a compound to compete for binding of an immobilized adenosine triphosphosphate (ATP) site directed ligand using a DNA-tagged vascular endothelial growth receptor 2 (VEGFR2) as the target. The ability of the test compound to compete with the immobilized ligand was measured using quantitative polymerase chain reaction (qPCR) of the DNA tag (Fabian, M. A. et al., 23 Nature Biotechnology 329-336 (2005); Karaman, M. W. et al., 26 Nature Biotechnology 127-132 (2008)).A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E. coli) derived from the BL21 strain. The E. coli were grown to log-phase, infected with VEGFR2 tagged T7 phage and then incubated with shaking at 32° C. until lysis. The lysate containing the kinase was then centrifuged and filtered to remove cell debris. Affinity resin for the VEGFR2 assay was prepared by treating Streptavidin-coated magnetic beads with a biotinylated small molecule ligand for 30 minutes at room temperature. The beads were blocked with excess biotin and then washed with blocking buffer (SEABLOCK (PIERCE), 1% bovine serum albumin, 0.17% phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol). The binding reaction was initiated by combining in a well of a polystyrene 96-well plate, DNA tagged VEGFR2, liganded affinity beads and the serial diluted test compound in 1× binding buffer (20% SEABLOCK, 0.17× phosphate buffered saline, 0.05% TWEEN 20, 6 mM dithiothreitol) in a final volume of 0.135 ml. The assay plates were incubated at room temperature with shaking for 1 hour and then the beads were washed with wash buffer (1× phosphate buffered saline, 0.05% TWEEN 20). The beads were re-suspended in elution buffer (1× phosphate buffered saline, 0.05% TWEEN 20, 0.05 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The VEGFR2 concentration in the eluate was measured using qPCR.An 11-point dose response curve of 3-fold serial diluted test compound starting at 1 μM was used to determine the VEGFR2 binding constant (Kd). The compounds were prepared in 100% DMSO at 100× the final test concentration and the diluted to 1× in the assay for final DMSO concentration of 1%. Binding constants were calculated with standard dose-response curve using the Hill equation with Hill slope set to −1. Curves were fit using a non-linear least square fit with the Levenberg-Marquardt algorithm.
- Receptor [35S] GTPgammaS Binding Assays: (S1P1 GTPgammaS/S1P3 GTPgammaS) Compounds were loaded in a 384 Falcon v-bottom plate (0.5 μl/well in a 11 point, 3-fold dilution). Membranes prepared from S1P1/CHO cells or EDG3-Gal5-bla HEK293T cells (EDG3 equivalent S1P3) were added to the compound plate (40 l/well, final protein 3 μg/well) with MULTIDROP. [35S]GTP (1250 Ci/mmol, Perkin Elmer) was diluted in assay buffer: 20 mM HEPES, pH7.5, 10 mM MgCl2, 150 mM NaCl, 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (Dithiothreitol), 10 μM GDP, 0.1% fatty acid free BSA, and 10 μg/ml Saponin to 0.4 nM. 40 μl of the [35S] GTP solution was added to the compound plate with a final concentration of 0.2 nM. The reaction was kept at room temperature for 45 min. At the end of incubation, all the mixtures in the compound plate were transferred to Millipore 384-well FB filter plates via the VELOCITY11 Vprep liquid handler. The filter plate was washed with water 4 times by using the manifold Embla plate washer and dried at 60° C. for 45 min. MicroScint 20 scintillation fluid (30 μl) was added to each well for counting on the Packard TOPCOUNT . EC50 is defined as the agonist concentration that corresponds to 50% of the Ymax (maximal response) obtained for each individual compound tested. The EC50 for Example 689 was determined to be 5.7 nM in the assay utilizing membranes prepared from S1P1/CHO cells. The EC50 for Example 689 was determined to be >2000 nM in the assay utilizing membranes prepared from EDG3-Gal5-bla HEK293T cells.A smaller value for GTPγS S1P1 EC50 value indicated greater activity for the compound in the GTPγS S1P1 binding assay. A larger value for the GTPγS S1P3 EC50 value indicated less activity in the GTPγS S1P3 binding assay. Example 689, which is the phosphate ester of Example 672, possessed activity as an agonist of S1P1 and is selective over S1P3. Example 697, which is the phosphate ester of Example 681, possessed activity as an agonist of S1P1 and is selective over S1P3. Thus the compounds of the present invention may be used in treating, preventing, or curing various S1P1 receptor-related conditions while reducing or minimizing the side effects due to S1P3 activity. The selectivity of the compounds of the present invention indicate their potential use in treating, preventing, or curing autoimmune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus, psoriasis, or vascular diseases, while reducing or minimizing possible side effects due to S1P3 activity. Other potential uses of the compounds of the present invention include minimizing or reducing rejection of transplanted organs, while reducing or minimizing side effects due to S1P3 activity.
- Receptor [35S] GTPgammaS Binding Assays: (S1P1 GTPgammaS/S1P3 GTPgammaS) Compounds were loaded in a 384 Falcon v-bottom plate (0.5 l/well in a 11 point, 3-fold dilution). Membranes prepared from S1P1/CHO cells or EDG3-Gal5-bla HEK293T cells (EDG3 equivalent S1P3) were added to the compound plate (40 l/well, final protein 3 μg/well) with MULTIDROP . [35S]GTP (1250 Ci/mmol, Perkin Elmer) was diluted in assay buffer: 20 mM HEPES, pH7.5, 10 mM MgCl2, 150 mM NaCl, 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (Dithiothreitol), 10 μM GDP, 0.1% fatty acid free BSA, and 10 μg/ml Saponin to 0.4 nM. 40 μl of the [35S] GTP solution was added to the compound plate with a final concentration of 0.2 nM. The reaction was kept at room temperature for 45 min. At the end of incubation, all the mixtures in the compound plate were transferred to Millipore 384-well FB filter plates via the VELOCITY11 Vprep liquid handler. The filter plate was washed with water 4 times by using the manifold Embla plate washer and dried at 60° C. for 45 min. MicroScint 20 scintillation fluid (30 μl) was added to each well for counting on the Packard TOPCOUNT . EC50 is defined as the agonist concentration that corresponds to 50% of the Ymax (maximal response) obtained for each individual compound tested. The EC50 for Example 689 was determined to be 5.7 nM in the assay utilizing membranes prepared from S1P1/CHO cells. The EC50 for Example 689 was determined to be >2000 nM in the assay utilizing membranes prepared from EDG3-Gal5-bla HEK293T cells.A smaller value for GTPγS S1P1 EC50 value indicated greater activity for the compound in the GTPγS S1P1 binding assay. A larger value for the GTPγS S1P3 EC50 value indicated less activity in the GTPγS S1P3 binding assay. Example 689, which is the phosphate ester of Example 672, possessed activity as an agonist of S1P1 and is selective over S1P3. Example 697, which is the phosphate ester of Example 681, possessed activity as an agonist of S1P1 and is selective over S1P3. Thus the compounds of the present invention may be used in treating, preventing, or curing various S1P1 receptor-related conditions while reducing or minimizing the side effects due to S1P3 activity. The selectivity of the compounds of the present invention indicate their potential use in treating, preventing, or curing autoimmune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus, psoriasis, or vascular diseases, while reducing or minimizing possible side effects due to S1P3 activity. Other potential uses of the compounds of the present invention include minimizing or reducing rejection of transplanted organs, while reducing or minimizing side effects due to S1P3 activity.