Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors

Rajeev S Bhide; James Neels; Lan-Ying Qin; Zheming Ruan; Sylwia Stachura; Carolyn Weigelt; John S Sack; Kevin Stefanski; Xiaomei Gu; Jenny H Xie; Christine B Goldstine; Stacey Skala; Donna L Pedicord; Stefan Ruepp; T G Murali Dhar; Percy H Carter; Luisa M Salter-Cid; Michael A Poss; Paul Davies

doi:10.1016/j.bmcl.2016.07.047

Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4256-60. doi: 10.1016/j.bmcl.2016.07.047. Epub 2016 Jul 21.

Authors

Rajeev S Bhide¹, James Neels², Lan-Ying Qin², Zheming Ruan², Sylwia Stachura², Carolyn Weigelt³, John S Sack³, Kevin Stefanski⁴, Xiaomei Gu⁴, Jenny H Xie⁵, Christine B Goldstine⁵, Stacey Skala⁵, Donna L Pedicord⁵, Stefan Ruepp⁴, T G Murali Dhar², Percy H Carter², Luisa M Salter-Cid⁵, Michael A Poss², Paul Davies⁵

Affiliations

¹ Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States. Electronic address: rajeev.bhide@bms.com.
² Discovery chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
³ Molecular structure and design, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
⁴ PCO discovery, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.
⁵ Immunoscience biology, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08534, United States.

PMID: 27476421
DOI: 10.1016/j.bmcl.2016.07.047

Abstract

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.

Keywords: PI3Kδ; Phosphatidylinositol-3 kinases; Pyrrolo[2,1-f][1,2,4]triazin-4-amine; Rheumatoid arthritis.

MeSH terms

Amines / chemistry*
Amines / metabolism
Amines / therapeutic use
Animals
Arthritis / drug therapy
Arthritis / metabolism
Arthritis / pathology
Binding Sites
Disease Models, Animal
Drug Evaluation, Preclinical
Inhibitory Concentration 50
Mice
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Binding
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / therapeutic use
Protein Structure, Tertiary
Structure-Activity Relationship
Triazines / chemistry*

Substances

Amines
Phosphoinositide-3 Kinase Inhibitors
Protein Isoforms
Protein Kinase Inhibitors
Triazines