Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities

J Med Chem. 2005 Dec 29;48(26):8194-208. doi: 10.1021/jm0506930.

Neeraj Mahindroo ¹, Chien-Fu Huang, Yi-Huei Peng, Chiung-Chiu Wang, Chun-Chen Liao, Tzu-Wen Lien, Santhosh Kumar Chittimalla, Wei-Jan Huang, Chia-Hua Chai, Ekambaranellore Prakash, Ching-Ping Chen, Tsu-An Hsu, Cheng-Hung Peng, I-Lin Lu, Ling-Hui Lee, Yi-Wei Chang, Wei-Cheng Chen, Yu-Chen Chou, Chiung-Tong Chen, Chandra M V Goparaju, Yuan-Shou Chen, Shih-Jung Lan, Ming-Chen Yu, Xin Chen, Yu-Sheng Chao, Su-Ying Wu, Hsing-Pang Hsieh

Affiliations

Affiliation

1 Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.

PMID: 16366601 DOI: 10.1021/jm0506930

Abstract

The synthesis and structure-activity relationship studies of novel indole derivatives as Peroxisome Proliferator-activated Receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKA(y) mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARgamma and could be an important moiety for the binding to the protein.

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