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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2009, 52, 8, 2587-2602
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Discovery of Novel Tricyclic Full Agonists for the G-Protein-Coupled Niacin Receptor 109A with Minimized Flushing in Rats

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Departments of Medicinal Chemistry, Cardiovascular Diseases, Pharmacology, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900
* To whom correspondence should be addressed. Address: Merck Research Laboratories, Mail Code RY121-252, P.O. Box 2000, 126 East Lincoln Avenue, Rahway, New Jersey 07065-0900. Phone: (732) 594-1755. Fax: (732) 594-9473. E-mail: [email protected]
†Department of Medicinal Chemistry.
‡Department of Cardiovascular Diseases.
§Department of Pharmacology.
#Department of Drug Metabolism.
Cite this: J. Med. Chem. 2009, 52, 8, 2587–2602
Publication Date (Web):March 23, 2009
https://doi.org/10.1021/jm900151e
Copyright © 2009 American Chemical Society
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Abstract

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Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

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Experimental procedures for compound preparation, characterization data, biological assay protocols, and LC/MS and 1H NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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