title: 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 alpha subtype-selective activators.
abstract: Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor alpha (PPARalpha) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the alpha-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 PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARalpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1 Mitarai, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nomura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanase
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ide
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsunoda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hideharu
authors.initials: H
authors.lastname: Uchiki
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D005230:Fatty Acids, Nonesterified; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002784:Cholesterol