Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives.
In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.
Furukawa
Akihiro
A
Shinagawa R&D Center, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, Japan. furukawa.akihiro.zy@daiichisankyo.co.jp
Arita
Tsuyoshi
T
Satoh
Susumu
S
Wakabayashi
Kenji
K
Hayashi
Shinko
S
Matsui
Yumi
Y
Araki
Kazushi
K
Kuroha
Masanori
M
Ohsumi
Jun
J
D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
D001572:Benzofurans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C085452:cercosporamide; D005947:Glucose