Synthesis and biological evaluation of novel (-)-Cercosporamide derivatives as potent selective PPARγ modulators.
Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.
Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Tokyo 140 8710, Japan. furukawa.akihiro.zy@daiichisankyo.co.jp
Akihiro
A
Furukawa
Tsuyoshi
T
Arita
Takehiro
T
Fukuzaki
Makoto
M
Mori
Takeshi
T
Honda
Susumu
S
Satoh
Yumi
Y
Matsui
Kenji
K
Wakabayashi
Shinko
S
Hayashi
Kouichi
K
Nakamura
Kazushi
K
Araki
Masanori
M
Kuroha
Jun
J
Tanaka
Satoko
S
Wakimoto
Osamu
O
Suzuki
Jun
J
Ohsumi
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats
D001572:Benzofurans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C085452:cercosporamide