Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors

Ping Chen; Derek Norris; Jagabandhu Das; Steven H Spergel; John Wityak; Leslie Leith; Rulin Zhao; Bang-Chi Chen; Sidney Pitt; Suhong Pang; Ding Ren Shen; Rosemary Zhang; Henry F De Fex; Arthur M Doweyko; Kim W McIntyre; David J Shuster; Kamelia Behnia; Gary L Schieven; Joel C Barrish

doi:10.1016/j.bmcl.2004.09.093

Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors

Bioorg Med Chem Lett. 2004 Dec 20;14(24):6061-6. doi: 10.1016/j.bmcl.2004.09.093.

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 15546730
DOI: 10.1016/j.bmcl.2004.09.093

Abstract

A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / pharmacokinetics
Amides / pharmacology*
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / pharmacokinetics
Anti-Inflammatory Agents / pharmacology*
Arthritis, Experimental / therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
Male
Models, Molecular
Molecular Structure
Rats
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / pharmacokinetics
Thiazoles / pharmacology*
src-Family Kinases / antagonists & inhibitors*

Substances

Amides
Anti-Inflammatory Agents
Enzyme Inhibitors
Thiazoles
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
src-Family Kinases