5Z6S

Crystal structure of the PPARgamma-LBD complexed with compound DS-6930

5Z6S の概要

• エントリーDOI: 10.2210/pdb5z6s/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, 3-[[6-(3,5-dimethylpyridin-2-yl)oxy-1-methyl-benzimidazol-2-yl]methoxy]benzoic acid, ... (5 entities in total)
• 機能のキーワード: transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34954.29

構造登録者

Matsui, Y.,Hanzawa, H. (登録日: 2018-01-25, 公開日: 2018-10-17, 最終更新日: 2023-11-22)

主引用文献

Shinozuka, T.,Tsukada, T.,Fujii, K.,Tokumaru, E.,Shimada, K.,Onishi, Y.,Matsui, Y.,Wakimoto, S.,Kuroha, M.,Ogata, T.,Araki, K.,Ohsumi, J.,Sawamura, R.,Watanabe, N.,Yamamoto, H.,Fujimoto, K.,Tani, Y.,Mori, M.,Tanaka, J.
Discovery of DS-6930, a potent selective PPAR gamma modulator. Part II: Lead optimization.
Bioorg. Med. Chem., 26:5099-5117, 2018

PubMed Abstract: Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients.

PubMed: 30220602
DOI: 10.1016/j.bmc.2018.09.005

実験手法

X-RAY DIFFRACTION (1.8 Å)