Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2- oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N 1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.Peer Reviewe

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.This work was supported by the Spanish Ministerio de Ciencia e Innovación grant SAF2009-09323. P. V.-A. held a FPI fellowship from the Ministerio de Ciencia e InnovaciónPeer Reviewe

Design, synthesis and biological evaluation of peptidomimetic ureas analogues of the thrombin receptor PAR1 antagonist RWJ-58259

Trabajo presentado en el XVI Congress SEQT: From a classical to a new age in medicinal chemistry, celebrado en Valencia (España) del 18 al 21 de septiembre de 2011.Thrombin regulates multiple cellular responses, such as platelet aggregation and tumor cell proliferation and angiogenesis. These cellular effects of thrombin are mediated by the activation of the protease-activated receptor PAR1. This activation unveils at the N-terminal exodomain of PAR1 the tethered activation ligand SFLLRN. First potent PAR1 antagonists were SFLLRN-based peptidomimetic ureas, represented by RWJ-58259 (Figure), which was the first antagonist that provided in vivo proof of the clinical utility of PAR1 antagonists in cardiovascular and tumoral diseases. Taking into account these precedents and recent structural studies on the thrombin/PAR1 interaction,3 a small and directed library of RWJ-58259 analogue ureas of general formula 1 has been design, synthesized and screened as PAR1 antagonists.This work was supported by the Spanish Ministry of Science and Innovation grants SAF2006-01205 and SAF2009-09323. P. V.-A. holds a FPI fellowship from the Spanish Ministry of Science and Innovation

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2- oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N 1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.Peer Reviewe