2. Academic Validation
  3. Structure-based design of novel 2-amino-6-phenyl-pyrimido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR, and in vivo anti-inflammatory activity

Structure-based design of novel 2-amino-6-phenyl-pyrimido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR, and in vivo anti-inflammatory activity

  • J Med Chem. 2008 Mar 27;51(6):1637-48. doi: 10.1021/jm701095m.
Matthew W Martin 1,  John Newcomb,  Joseph J Nunes,  Christina Boucher,  Lilly Chai,  Linda F Epstein,  Theodore Faust,  Sylvia Flores,  Paul Gallant,  Anu Gore,  Yan Gu,  Faye Hsieh,  Xin Huang,  Joseph L Kim,  Scot Middleton,  Kurt Morgenstern,  Antonio Oliveira-dos-Santos,  Vinod F Patel,  David Powers,  Paul Rose,  Yanyan Tudor,  Susan M Turci,  Andrew A Welcher,  Debra Zack,  Huilin Zhao,  Li Zhu,  Xiaotian Zhu,  Chiara Ghiron,  Monika Ermann,  David Johnston,  Carl-Gustaf Pierre Saluste
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. matmarti@amgen.com
PMID: 18278858 DOI: 10.1021/jm701095m
Abstract

Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading 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 structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.

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