Himbacine-Derived Thrombin Receptor Antagonists: C7-Aminomethyl and C9a-Hydroxy Analogues of Vorapaxar

Autor:	Stan Kurowski, Mariappan V. Chelliah, William J. Greenlee, Madhu Chintala, Yunsheng Hsieh, Yan Xia, George Boykow, Ho-Sam Ahn, Samuel Chackalamannil
Rok vydání:	2013
Předmět:	Platelet aggregation business.industry education Organic Chemistry Pharmacology Biochemistry humanities In vitro binding chemistry.chemical_compound Par 1 antagonist chemistry Pharmacokinetics Himbacine Drug Discovery Thrombin receptor medicine business Ex vivo Vorapaxar medicine.drug
Zdroj:	ACS Medicinal Chemistry Letters. 5:183-187
ISSN:	1948-5875
DOI:	10.1021/ml400452v
Popis:	We have synthesized several C7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K i = 5 nM). We have also synthesized a C9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::64b51fb9c036df9fa0fa9ec39ff0de40 https://doi.org/10.1021/ml400452v Zobrazit plný text záznamu