Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry–activity relationship

• Published in: Bioorganic & medicinal chemistry 2012-11, Vol.20 (21), p.6375-6383
• Main Authors: Ohashi, Masao, Nakagome, Izumi, Kasuga, Jun-ichi, Nobusada, Hiromi, Matsuno, Kenji, Makishima, Makoto, Hirono, Shuichi, Hashimoto, Yuichi, Miyachi, Hiroyuki
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Dose-Response Relationship, Drug; Drug Design; Humans; Medical sciences; Models, Molecular; Molecular Structure; Peroxisome proliferator-activated receptor; Pharmacology. Drug treatments; Phenylpropanoic acid; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Phenylpropionates - pharmacology; PPAR; PPAR gamma - agonists; PPAR gamma - metabolism; PPARγ; SAR; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.08.061

We previously demonstrated that the α-benzylphenylpropanoic acid-type PPARγ-selective agonist 6 exhibited a reversed stereochemistry–activity relationship, that is, the (R)-enantiomer is a more potent PPARγ agonist than the (S)-enantiomer, compared with structurally similar α-ethylphenylpropanoic acid-type PPAR agonists. Here, we designed, synthesized and evaluated the optically active α-cyclohexylmethylphenylpropanoic acid derivatives 7 and α-phenethylphenylpropanoic acid derivatives 8, respectively. Interestingly, α-cyclohexylmethyl derivatives showed reversal of the stereochemistry–activity relationship [i.e., (R) more potent than (S)], like α-benzyl derivatives, whereas α-phenethyl derivatives showed the ‘normal’ relationship [(S) more potent than (R)]. These results suggested that the presence of a branched carbon atom at the β-position with respect to the carboxyl group is a critical determinant of the reversed stereochemistry–activity relationship.