4F9M

Crystal structure of the PPARgamma-LBD complexed with a cercosporamide derivative modulator

Summary for 4F9M

• Entry DOI: 10.2210/pdb4f9m/pdb
• Related: 3B1M 3LMP 3V9T 3V9V 3V9Y
• Descriptor: Peroxisome proliferator-activated receptor gamma, peptide from Nuclear receptor coactivator 1, (9aS)-8-acetyl-N-[(2-ethyl-4-fluoronaphthalen-1-yl)methyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-carboxamide, ... (4 entities in total)
• Functional Keywords: three-layered alpha-helical sandwich, transcription regulation, transcription-transcription regulator complex, transcription/transcription regulator
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P37231; Nucleus (By similarity): Q15788
• Total number of polymer chains: 2
• Total formula weight: 34720.18

Authors

Matsui, Y.,Hanzawa, H. (deposition date: 2012-05-19, release date: 2012-08-08, Last modification date: 2023-11-08)

Primary citation

Furukawa, A.,Arita, T.,Fukuzaki, T.,Mori, M.,Honda, T.,Satoh, S.,Matsui, Y.,Wakabayashi, K.,Hayashi, S.,Nakamura, K.,Araki, K.,Kuroha, M.,Tanaka, J.,Wakimoto, S.,Suzuki, O.,Ohsumi, J.
Synthesis and biological evaluation of novel (-)-cercosporamide derivatives as potent selective PPARg modulators
Eur.J.Med.Chem., 54:522-533, 2012

PubMed 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.

PubMed: 22727448
DOI: 10.1016/j.ejmech.2012.05.040

Experimental method

X-RAY DIFFRACTION (1.9 Å)