Synthesis and biological evaluation of novel (-)-Cercosporamide derivatives as potent selective PPARγ modulators.

Akihiro Furukawa, Tsuyoshi Arita, Takehiro Fukuzaki, Makoto Mori, Takeshi Honda, Susumu Satoh, Yumi Matsui, Kenji Wakabayashi, Shinko Hayashi, Kouichi Nakamura, Kazushi Araki, Masanori Kuroha, Jun Tanaka, Satoko Wakimoto, Osamu Suzuki, Jun Ohsumi

Index: Eur. J. Med. Chem. 54 , 522-33, (2012)

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Abstract

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.Copyright © 2012 Elsevier Masson SAS. All rights reserved.