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Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A).

Abstract：

:Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 Å and out-of-plane orientation of the larger substituents.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

van Veldhoven JP,Blad CC,Artsen CM,Klopman C,Wolfram DR,Abdelkadir MJ,Lane JR,Brussee J,Ijzerman AP

doi

10.1016/j.bmcl.2010.11.091

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

2736-9

issue

9

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)01716-6

journal_volume

21

pub_type

杂志文章

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