Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor α subtype-selective activators

Masahiro Nomura, Takahiro Tanase, Tomohiro Ide, Masaki Tsunoda, Masahiro Suzuki, Hideharu Uchiki, Koji Murakami, Hiroyuki Miyachi

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor α (PPARα) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the α-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARα selective optically active α-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARα but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.

Original languageEnglish
Pages (from-to)3581-3599
Number of pages19
JournalJournal of medicinal chemistry
Volume46
Issue number17
DOIs
Publication statusPublished - Aug 14 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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