Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety

Replacement of the noragmatine group in thrombin inhibitors with a ß-alanyl-guanidine group resulted in a nearly equipotent and more selective compound 8 despite the fact that the pK_a of this P₁ moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor with this ß-alanyl-guanidine group, compound 28. This is an active and selective thrombin inhibitor and in view of its nonpeptide/low basicity structure selected for further pharmacological studies.