Exploration of a new series of PAR1 antagonists.

Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented.

Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo.

Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1.

From pure FPP to mixed FPP and CAAX competitive inhibitors of farnesyl protein transferase.

Starting from a FPP analogue with nanomolar inhibitory activity against isolated FPTase, yet lacking activity in cellular assays, structural modifications were performed to enhance cellular activity by removing all acidic functionalities. Overall, these changes resulted in the transformation of a pure FPP to a mixed FPP and CAAX competitive inhibitor with nanomolar activity on isolated FPTase and micromolar inhibitory activity in the farnesylation of H-Ras in cultured DLD-1 cells.

Synthesis and evaluation of a novel series of farnesyl protein transferase inhibitors as non-peptidic CAAX tetrapeptide analogues.

A novel series of compounds, derived from 4-amino-phenyl piperazine, has been designed to selectively inhibit farnesyl protein transferase (FPTase) as CAAX tetrapeptide analogues. Certain of these compounds were shown to possess low nanomolar inhibitory activity both against the isolated enzyme and in cultured cells.

Solid-phase preparation of hydantoins through a new cyclization/cleavage step.

An efficient process for the solid-phase synthesis of hydantoins has been developed. The amino acid starting material is anchored to the resin from its carboxylic acid end through formation of a very stable amide bond. After introduction of different functional groups, the cleavage/cyclization step can be performed in acidic or basic conditions.