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

Neeraj Mahindroo, 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 GoparajuYuan Shou Chen, Shih Jung Lan, Ming Chen Yu, Xin Chen, Yu Sheng Chao, Su Ying Wu, Hsing Pang Hsieh

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71 Citations (Scopus)

Abstract

The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a druglike 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 PPARγ 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 KKAy mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARγ and could be an important moiety for the binding to the protein.

Original languageEnglish
Pages (from-to)8194-8208
Number of pages15
JournalJournal of Medicinal Chemistry
Volume48
Issue number26
DOIs
Publication statusPublished - Dec 29 2005
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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  • Cite this

    Mahindroo, N., Huang, C. F., Peng, Y. H., Wang, C. C., Liao, C. C., Lien, T. W., Chittimalla, S. K., Huang, W. J., Chai, C. H., Prakash, E., Chen, C. P., Hsu, T. A., Peng, C. H., Lu, I. L., Lee, L. H., Chang, Y. W., Chen, W. C., Chou, Y. C., Chen, C. T., ... Hsieh, H. P. (2005). Novel indole-based peroxisome proliferator-activated receptor agonists: Design, SAR, structural biology, and biological activities. Journal of Medicinal Chemistry, 48(26), 8194-8208. https://doi.org/10.1021/jm0506930