Design and synthesis of thrombin receptor-derived nonpeptide mimetics utilizing a piperazine scaffold

Focal thrombus formation and vasoconstriction serve to defend vessels when vascular damage occurs, but may be detrimental when an atherosclerotic plaq ue is disrupted. Recently, the identification of the platelet thrombin rece ptor opened a new area in the development of agents that may selectively in hibit the effects of thrombin on cells, without affecting fibrin formation. In this regard, we have synthesized a number of 1,4-disubstituted piperazi nes which are designed to be analogues of thrombin receptor activating pept ides (TRAP) and carry the pharmacophoric features of Phe and Arg residues p resent in the active pentapeptide SFLLR. These compounds were tested in the rat aorta relaxation assay and in platelet aggregation studies and their b iological activity was consistent with a direct action on thrombin receptor . Furthermore, the structure-activity relationships confirmed the importanc e of Phe and Arg for receptor activation and the molecular modeling reveale d an intriguing relationship between their amphipathic similarity with SFLL R and their biological activity. (C) 1999 Elsevier Science Ltd. All rights reserved.