Discovery and initial SAR of imidazoquinoxalines as inhibitors of the Src-family kinase p56(Lck)

Ping Chen; Derek Norris; Edwin J Iwanowicz; Steven H Spergel; James Lin; Henry H Gu; Zhongqi Shen; John Wityak; Tai-An Lin; Suhong Pang; Henry F De Fex; Sidney Pitt; Ding Ren Shen; Arthur M Doweyko; Donna A Bassolino; Jacques Y Roberge; Michael A Poss; Bang-Chi Chen; Gary L Schieven; Joel C Barrish

doi:10.1016/s0960-894x(02)00191-9

Discovery and initial SAR of imidazoquinoxalines as inhibitors of the Src-family kinase p56(Lck)

Bioorg Med Chem Lett. 2002 May 20;12(10):1361-4. doi: 10.1016/s0960-894x(02)00191-9.

Affiliation

¹ Department of Discovery Chemistry, Bristol Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. ping.chen@bms.com

PMID: 11992777
DOI: 10.1016/s0960-894x(02)00191-9

Abstract

We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.

MeSH terms

Animals
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Kinetics
Lymphocyte Activation / drug effects
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
Models, Molecular
Molecular Conformation
Quinoxalines / chemical synthesis*
Quinoxalines / pharmacology
Structure-Activity Relationship
T-Lymphocytes / drug effects
T-Lymphocytes / enzymology
T-Lymphocytes / immunology
src-Family Kinases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Imidazoles
Quinoxalines
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
src-Family Kinases