Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent

Autor:	Robert P. Rehfuss, Paul Levesque, Juliang Zhu, Arvind Mathur, Dietmar A. Seiffert, Bang-Chi Chen, Rejean Ruel, Laura Price, Yufeng Wang, Mary F. Malley, Xue-Qing Chen, Wu Yang, Ji Hua, Tammy C. Wang, William A. Schumacher, Yajun Liu, Dauh-Rurng Wu, Silvi A. Chacko, Jeffrey S. Bostwick, Charles G. Clark, Danshi Li, Patrick Y.S. Lam, Henry S. Wong, Anne B. Stewart, Dawn Sun, Ruth R. Wexler, Hong Shen, Sheldon Hiebert, Christine Huang, Ling Li, Jeon Yoon T, Carl Thibeault, Jennifer X. Qiao
Rok vydání:	2013
Předmět:	Platelet Aggregation Stereochemistry Clinical Biochemistry Pharmaceutical Science Administration Oral Biochemistry chemistry.chemical_compound Receptors Purinergic P2Y1 Structure-Activity Relationship P2Y12 Dogs In vivo Drug Discovery Antithrombotic Potency Animals Urea Molecular Biology Indole test Chemistry Phenylurea Compounds Organic Chemistry Antagonist Thrombosis Rats Macaca fascicularis Thiazoles Purinergic P2Y Receptor Antagonists Molecular Medicine Piperidine Platelet Aggregation Inhibitors Half-Life
Zdroj:	Bioorganicmedicinal chemistry letters. 24(5)
ISSN:	1464-3405
Popis:	Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d87ed0cd8e9411cf0132670a06c19e56 https://pubmed.ncbi.nlm.nih.gov/24513044 Zobrazit plný text záznamu Full Text from ScienceDirect