1,2-Disubstituted cyclohexane derived tripeptide aldehydes as novel selective thrombin inhibitors

A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor. Two series of tripeptide arginine aldehydes Ph(CH 2) nNH(Me)-1,2-COcC 6H 10COArgH and D-MePhe-1,2-(CONH)cC 6H 10COArgH bearing a central 1,2-disubstituted cyclohexane moiety of defined stereochemistry were synthesized and screened for thrombin inhibition activity. Later modification of the aromatic side chain in the light of modeling studies led to the potent and selective inhibitor 13e.