Home LiteratureArticle Details

PMID: 17994679 Published · ppublish English Journal Article

Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.

Journal of medicinal chemistry ·Vol. 50 ·No. 25 ·2007-12-13 ·Pages 6303-6

Shen HC, Ding FX, Luell S, Forrest MJ, Carballo-Jane E, Wu KK, Wu TJ, Cheng K, Wilsie LC, Krsmanovic ML, Taggart AK, Ren N, Cai TQ, Deng Q, Chen Q, Wang J, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, Colletti SL

Abstract

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.

MeSH Terms

Amides/chemical synthesis,pharmacokinetics,pharmacology Animals Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors Binding, Competitive CHO Cells Cricetinae Cricetulus Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2C9 Humans In Vitro Techniques Mice Microsomes, Liver/metabolism Radioligand Assay Receptors, G-Protein-Coupled/agonists Receptors, Nicotinic Structure-Activity Relationship ortho-Aminobenzoates/chemical synthesis,pharmacokinetics,pharmacology

Chemicals

Amides HCAR2 protein, human HCAR3 protein, human Receptors, G-Protein-Coupled Receptors, Nicotinic ortho-Aminobenzoates CYP2C9 protein, human Cytochrome P-450 CYP2C9 Aryl Hydrocarbon Hydroxylases CYP2C8 protein, human Cytochrome P-450 CYP2C8

Authors & Affiliations

23 authors, click to expand affiliations / ORCID

Shen Hong C

Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. hong_shen@merck.com

Ding Fa-Xiang

Luell Silvi

Forrest Michael J

Carballo-Jane Ester

Wu Kenneth K

Wu Tsuei-Ju

Cheng Kang

Wilsie Larissa C

Krsmanovic Mihajlo L

Taggart Andrew K

Ren Ning

Cai Tian-Quan

Deng Qiaolin

Chen Qing

Wang Junying

Wolff Michael S

Tong Xinchun

Holt Tom G

Waters M Gerard

Hammond Milton L

Tata James R

Colletti Steven L

Article Info

Journal

Journal of medicinal chemistry

Abbr.

J Med Chem

ISSN

0022-2623

DOI

10.1021/jm700942d

hong_shen@merck.com

Published

2007-12-13

Epub

2007-00-10

Pages

6303-6

Language

English

Region

United States

NLM ID

9716531

Subset

External Links

PubMed source DOI: 10.1021/jm700942d View journal details

Analysis Services

Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.

Contact

WeChat Official Account