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

• Published in: European journal of medicinal chemistry Vol. 70; pp. 199 - 224
• Main Authors: Valdivielso, Ángel M., Ventosa-Andrés, Pilar, Tato, Francisco, Fernández-Ibañez, M. Ángeles, Pappos, Ioannis, Tsopanoglou, Nikos E., García-López, M. Teresa, Gutiérrez-Rodríguez, Marta, Herranz, Rosario
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2013; Elsevier
• Subjects: 2-Oxopiperazines; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Life Sciences & Biomedicine; Molecular Conformation; PAR1 antagonists; Peptidomimetics; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Platelet Aggregation - drug effects; Platelet antiaggregant activity; Receptor, PAR-1 - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; α-Amino nitriles; α-Amino nitriles; PAR1 antagonists; Cytotoxicity; Platelet antiaggregant activity; Peptidomimetics; 2-Oxopiperazines; alpha-Amino nitriles; IDENTIFICATION; CANCER; DISCOVERY; POTENT; THROMBIN-RECEPTOR; VORAPAXAR; PROTEASE-ACTIVATED-RECEPTOR-1 PAR1; DIFFERENTIATION; PROTEASE-ACTIVATED RECEPTOR-1; EXPRESSION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.09.058

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-, N1-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. [Display omitted] •Chiral tetrasubstituted-2-oxopiperazines have been designed as PAR1 antagonists.•Highly functionalized piperazines have been synthesized from pseudodipeptides.•Moderate platelet antiaggregant PAR1 antagonists have been found.•New micromolar cytotoxic agents for human cancer cells have been identified.