Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A

Hong C Shen; Michael J Szymonifka; Divya Kharbanda; Qiaolin Deng; Ester Carballo-Jane; Kenneth K Wu; Tsuei-Ju Wu; Kang Cheng; Ning Ren; Tian-Quan Cai; Andrew K Taggart; Junying Wang; Xinchun Tong; M Gerard Waters; Milton L Hammond; James R Tata; Steven L Colletti

doi:10.1016/j.bmcl.2007.10.055

Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6723-8. doi: 10.1016/j.bmcl.2007.10.055. Epub 2007 Oct 18.

Authors

Hong C Shen¹, Michael J Szymonifka, Divya Kharbanda, Qiaolin Deng, Ester Carballo-Jane, Kenneth K Wu, Tsuei-Ju Wu, Kang Cheng, Ning Ren, Tian-Quan Cai, Andrew K Taggart, Junying Wang, Xinchun Tong, 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. [email protected]

PMID: 18029181
DOI: 10.1016/j.bmcl.2007.10.055

Abstract

A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.

MeSH terms

Animals
Combinatorial Chemistry Techniques
Humans
Male
Mice
Models, Animal
Molecular Structure
Niacin / pharmacology*
Receptors, G-Protein-Coupled / agonists*
Receptors, Nicotinic
Structure-Activity Relationship
Urea* / analogs & derivatives
Urea* / chemical synthesis
Urea* / chemistry
Urea* / pharmacokinetics
Vasodilation / drug effects

Substances

Hcar2 protein, mouse
Receptors, G-Protein-Coupled
Receptors, Nicotinic
Niacin
Urea