N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR

Holly L Deak; John R Newcomb; Joseph J Nunes; Christina Boucher; Alan C Cheng; Erin F DiMauro; Linda F Epstein; Paul Gallant; Brian L Hodous; Xin Huang; Josie H Lee; Vinod F Patel; Stephen Schneider; Susan M Turci; Xiaotian Zhu

doi:10.1016/j.bmcl.2007.11.123

N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR

Bioorg Med Chem Lett. 2008 Feb 1;18(3):1172-6. doi: 10.1016/j.bmcl.2007.11.123. Epub 2007 Dec 5.

Authors

Holly L Deak¹, John R Newcomb, Joseph J Nunes, Christina Boucher, Alan C Cheng, Erin F DiMauro, Linda F Epstein, Paul Gallant, Brian L Hodous, Xin Huang, Josie H Lee, Vinod F Patel, Stephen Schneider, Susan M Turci, Xiaotian Zhu

Affiliation

¹ Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. [email protected]

PMID: 18083554
DOI: 10.1016/j.bmcl.2007.11.123

Abstract

N-3-(Phenylcarbamoyl)arylpyrimidine-5-carboxamides are a novel class of selective Lck inhibitors. This series of compounds derives its selectivity from a hydrogen bond with the gatekeeper Thr316 of the enzyme. X-ray co-crystal structural data, structure-activity relationships, and the synthesis of these inhibitors are reported herein.

MeSH terms

Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology*
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Drug Design
Humans
Hydrogen Bonding
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
Molecular Conformation
Molecular Structure
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Threonine / chemistry

Substances

Amides
Pyrimidines
Threonine
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)