Bioorganic & Medicinal Chemistry Letters 2011-05-01

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

J P D van Veldhoven, C C Blad, C M Artsen, C Klopman, D R Wolfram, M J Abdelkadir, J R Lane, J Brussee, A P Ijzerman

Index: Bioorg. Med. Chem. Lett. 21 , 2736-9, (2011)

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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.Copyright © 2010 Elsevier Ltd. All rights reserved.