Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity

  • J Med Chem. 2006 Sep 21;49(19):5671-86. doi: 10.1021/jm0605482.
Erin F DiMauro  1 ,  John Newcomb ,  Joseph J Nunes ,  Jean E Bemis ,  Christina Boucher ,  John L Buchanan ,  William H Buckner ,  Victor J Cee ,  Lilly Chai ,  Holly L Deak ,  Linda F Epstein ,  Ted Faust ,  Paul Gallant ,  Stephanie D Geuns-Meyer ,  Anu Gore ,  Yan Gu ,  Brad Henkle ,  Brian L Hodous ,  Faye Hsieh ,  Xin Huang ,  Joseph L Kim ,  Josie H Lee ,  Matthew W Martin ,  Craig E Masse ,  David C McGowan ,  Daniela Metz ,  Deanna Mohn ,  Kurt A Morgenstern ,  Antonio Oliveira-dos-Santos ,  Vinod F Patel ,  David Powers ,  Paul E Rose ,  Stephen Schneider ,  Susan A Tomlinson ,  Yan-Yan Tudor ,  Susan M Turci ,  Andrew A Welcher ,  Ryan D White ,  Huilin Zhao ,  Li Zhu ,  Xiaotian Zhu
Affiliations
  • 1. Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts 02139, USA. [email protected]
PMID: 16970394 DOI: 10.1021/jm0605482
Abstract

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (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. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

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