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.
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.
Nomura
Masahiro
M
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1 Mitarai, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Tanase
Takahiro
T
Ide
Tomohiro
T
Tsunoda
Masaki
M
Suzuki
Masahiro
M
Uchiki
Hideharu
H
Murakami
Koji
K
Miyachi
Hiroyuki
H
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
D005230:Fatty Acids, Nonesterified; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002784:Cholesterol