Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A

Fa-Xiang Ding; Hong C Shen; Larrisa C Wilsie; Mihajlo L Krsmanovic; Andrew K Taggart; Ning Ren; Tian-Quan Cai; Junying Wang; Xinchun Tong; Tom G Holt; Qing Chen; M Gerard Waters; Milton L Hammond; James R Tata; Steven L Colletti

doi:10.1016/j.bmcl.2010.04.013

Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A

Bioorg Med Chem Lett. 2010 Jun 1;20(11):3372-5. doi: 10.1016/j.bmcl.2010.04.013. Epub 2010 Apr 11.

Authors

Fa-Xiang Ding¹, Hong C Shen, Larrisa C Wilsie, Mihajlo L Krsmanovic, Andrew K Taggart, Ning Ren, Tian-Quan Cai, Junying Wang, Xinchun Tong, Tom G Holt, Qing Chen, M Gerard Waters, Milton L Hammond, James R Tata, Steven L Colletti

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. fa_xiang_ding@merck.com

PMID: 20452209
DOI: 10.1016/j.bmcl.2010.04.013

Abstract

A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.

MeSH terms

Amides / chemistry*
Animals
Cyclohexenes / chemistry
Cyclohexenes / pharmacokinetics
Cyclohexenes / pharmacology*
Mice
Rats
Receptors, G-Protein-Coupled / agonists*
Receptors, Nicotinic
Structure-Activity Relationship

Substances

Amides
Cyclohexenes
HCAR2 protein, human
Receptors, G-Protein-Coupled
Receptors, Nicotinic
cyclohexene