Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity PMID: 16884310

Target-related Cytokines

2026-09-23

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity

J Med Chem. 2006 Aug 10;49(16):4981-91. doi: 10.1021/jm060435i.

Matthew W Martin ¹ , John Newcomb , Joseph J Nunes , David C McGowan , David M Armistead , Christina Boucher , John L Buchanan , William Buckner , Lilly Chai , Daniel Elbaum , Linda F Epstein , Theodore Faust , Shaun Flynn , Paul Gallant , Anu Gore , Yan Gu , Faye Hsieh , Xin Huang , Josie H Lee , Daniela Metz , Scot Middleton , Deanna Mohn , Kurt Morgenstern , Michael J Morrison , Perry M Novak , Antonio Oliveira-dos-Santos , David Powers , Paul Rose , Stephen Schneider , Stephanie Sell , Yanyan Tudor , Susan M Turci , Andrew A Welcher , Ryan D White , Debra Zack , Huilin Zhao , Li Zhu , Xiaotian Zhu , Chiara Ghiron , Patricia Amouzegh , Monika Ermann , James Jenkins , David Johnston , Spencer Napier , Eoin Power

Affiliations

Abstract

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.