Synthesis and biological activity of novel alpha-substituted beta-phenylpropionic acids having pyridin-2-ylphenyl moiety as antihyperglycemic agents.
We previously reported the identification of novel oximes having 5-benzyl-2,4-thiazolidinedione with antihyperglycemic activity. We now report the synthesis and biological activity of a novel series of oximes and amides having alpha-substituted-beta-phenylpropionic acids. In this series, we obtained potent PPAR alpha/gamma dual agonist (S)-9d, with which activation of PPAR alpha and PPAR gamma was considerably more potent than that of the reference compounds GW9578 22 and rosiglitazone 3, respectively. This means (S)-9d is of the strongest class of PPAR alpha/gamma dual agonists. In the course of this study, we also obtained 8h, which indicated potent plasma glucose lowering effect in spite of weak PPAR alpha/gamma agonistic activity.
Takamura
Makoto
M
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. takamu@shina.sankyo.co.jp
Sakurai
Mitsuya
M
Yamada
Eriko
E
Fujita
Sachie
S
Yachi
Makoto
M
Takagi
Toshiyuki
T
Isobe
Aya
A
Hagisawa
Yuka
Y
Fujiwara
Toshihiko
T
Yanagisawa
Hiroaki
H
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis
D017931:DNA Primers; D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D010666:Phenylpropionates; D011725:Pyridines; C035253:3-phenylpropionic acid