Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P-1 moiety

Replacement of the noragmatine group in thrombin inhibitors with a beta-ala nyl-guanidine group resulted in a nearly equipotent and more selective comp ound 8 despite the fact that the pK(a) of this P-1 moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor w ith this beta-alanyl guanidine group, compound 28. This is an active and se lective thrombin inhibitor and in view of its nonpeptide/low basicity struc ture selected for further pharmacological studies. (C) 1998 Elsevier Scienc e Ltd. All rights reserved.