Conformationally Constrained ortho-Anilino Diaryl Ureas: Discovery of 1‑(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y1 Antagonist

• Published in: Journal of medicinal chemistry Vol. 56; no. 22; pp. 9275 - 9295
• Main Authors: Qiao, Jennifer X, Wang, Tammy C, Ruel, Réjean, Thibeault, Carl, L’Heureux, Alexandre, Schumacher, William A, Spronk, Steven A, Hiebert, Sheldon, Bouthillier, Gilles, Lloyd, John, Pi, Zulan, Schnur, Dora M, Abell, Lynn M, Hua, Ji, Price, Laura A, Liu, Eddie, Wu, Qimin, Steinbacher, Thomas E, Bostwick, Jeffrey S, Chang, Ming, Zheng, Joanna, Gao, Qi, Ma, Baoqing, McDonnell, Patricia A, Huang, Christine S, Rehfuss, Robert, Wexler, Ruth R, Lam, Patrick Y. S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.11.2013
• Subjects: Animals; Biological Availability; Drug Design; Humans; Indoles - chemistry; Models, Molecular; Molecular Conformation; Phenylurea Compounds - chemistry; Phenylurea Compounds - metabolism; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Purinergic P2Y Receptor Antagonists - chemistry; Purinergic P2Y Receptor Antagonists - metabolism; Purinergic P2Y Receptor Antagonists - pharmacokinetics; Purinergic P2Y Receptor Antagonists - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2Y1 - chemistry; Receptors, Purinergic P2Y1 - metabolism; Sequence Homology, Amino Acid; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Urea - chemistry; Urea - metabolism; Urea - pharmacokinetics; Urea - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4013906

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.