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 P2Y(1) Antagonist

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y(1) antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y(12) antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the...

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Published inJournal of medicinal chemistry Vol. 56; no. 22; pp. 9275 - 9295
Main Authors Qiao, Jennifer X., Wang, Tammy C., Ruel, Rejean, 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
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 28.11.2013
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
P2 RECEPTORS
ADP RECEPTORS
EXTRACELLULAR LOOPS
RECOGNITION
PLATELET-AGGREGATION
SMALL-MOLECULE
THROMBOSIS
HIGH-AFFINITY
PROTEIN-COUPLED RECEPTORS
DERIVATIVES
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Summary:Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y(1) antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y(12) 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 P2Y(1) antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 31 will also be presented. Compound 31 was our first P2Y(1) antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4013906