CVS-1578

Although CVS 1123 [PrPent-Asp(OMe)-Pro-Arg-H] and other peptidyl argininals have shown good thrombin inhibitory activity, oral bioavailability, and selectivity against related serine proteases, including plasmin and coagulation factors VIIa and Xa, they generally lack selectivity against trypsin.One strategy for achieving enhanced selectivity against trypsin was to focus on improving thrombin binding affinity by increasing conformational rigidity of the peptidic backbone present in inhibitors.We also reasoned that inhibitors which exploit a unique interaction with thrombin's 60 loop might lead to drug candidates with improved selectivity profiles.Since they can mimic partial type II/II' β-turn conformations, we pursued a series of novel thrombin inhibitors which incorporate lactam moieties as dipeptide surrogates.