Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 9; pp. 1459 - 1463
• Main Authors: Islam, Imadul, Yuan, Shendong, Wei, Robert G., Xu, Wei, Morrissey, Michael, Mohan, Raju, Zheng, Dewan, DiMella, Andrea, Dunning, Laura, Snider, Michael, Subramanyam, Babu, Tseng, Jih-Lie, Bryant, Judi A., Buckman, Brad O.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.05.2018; Elsevier
• Subjects: Administration, Oral; ADP; Animals; Antiplatelet therapy; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dogs; Dose-Response Relationship, Drug; Fluorenes - administration & dosage; Fluorenes - chemistry; Fluorenes - pharmacology; High-Throughput Screening Assays; HTS; Humans; Life Sciences & Biomedicine; Microsomes, Liver - metabolism; Molecular Structure; P2Y12 antagonists; Parallel synthesis; Pharmacology & Pharmacy; Physical Sciences; Platelet Aggregation - drug effects; Rats; Receptors, Purinergic P2Y12 - metabolism; Science & Technology; Structure-Activity Relationship; Antiplatelet therapy; Parallel synthesis; ADP; P2Y12 antagonists; HTS; RAT; PLATELET-AGGREGATION; IDENTIFICATION; ASPIRIN; CLOPIDOGREL; INHIBITION; P2Y antagonists; RESISTANCE; ACTIVE METABOLITE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.03.090

[Display omitted] •A hit to lead process to discover reversible, orally available ADP receptor (P2Y12) antagonists has been described.•Parallel synthesis, methyl scan of the hit enhances the discovery of new analogs.•Exploratory SAR provided orally available, competitive, reversible antagonists of P2Y12 receptor.•Two analogs show high metabolic stability in liver microsomes and found to be orally absorbed. A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KB = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class.