Design and synthesis of thrombin inhibitors: Analogues of MD-805 with reduced stereogenicity and improved potency

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which con tains four stereogenic centers, has been the starting point for an optimiza tion program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the origi nal lead. A number of 4-substituted piperidines were synthesized and examin ed as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpip eridine (FEP) among others provided inhibitors (e.g. 45g) of increased pote ncy. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahy droquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided supp ort, with modeling studies, for the preparation of the gem 3,3-disubstitute d compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3 ,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and s howed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhib itor (42e) was shown to produce a dose-dependent inhibition of thrombus for mation that in some situations was superior to that of MD-805.