Bicyclic compounds as ring-constrained inhibitors of protein-tyrosine kinase p56lck.

A study was undertaken to prepare inhibitors of the lymphocyte protein-tyrosine kinase p56lck. Using the known p56lck inhibitor 3,4-dihydroxy-alpha-cyanocinnamamide (4) as a lead compound, bicyclic analogues were designed as conformationally constrained mimetics in which the phenyl ring and vinyl side chain of the cinnamamide are locked into a coplanar orientation. Such planarity was rationalized to be an important determinant for binding within a putative flat, cleftlike catalytic cavity. Bicyclic analogues were prepared using the naphthalene, quinoline, isoquinoline, and 2-iminochromene ring systems and examined for their ability to inhibit autophosphorylation of immunopurified p56lck. The most potent analogues were methyl 7,8-dihydroxyisoquinoline-3-carboxylate (12) (IC50 = 0.2 microM) and 7,8-dihydroxyisoquinoline-3-carboxamide (13) (IC50 = 0.5 microM). Inhibition by 12 was not competitive with respect to ATP. These compounds may represent important new structural motifs for the development of p56lck inhibitors.