Document Report Card

ID: ALA1136753

Journal: J Med Chem

Title: Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase.

Authors: Goldberg DR, Butz T, Cardozo MG, Eckner RJ, Hammach A, Huang J, Jakes S, Kapadia S, Kashem M, Lukas S, Morwick TM, Panzenbeck M, Patel U, Pav S, Peet GW, Peterson JD, Prokopowicz AS, Snow RJ, Sellati R, Takahashi H, Tan J, Tschantz MA, Wang XJ, Wang Y, Wolak J, Xiong P, Moss N.

Abstract: The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.

CiteXplore: 12672234

DOI: 10.1021/jm020446l