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

Research output: Contribution to journalArticle

69 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

Fingerprint

Peroxisome Proliferator-Activated Receptors
Bioactivity
Tail
Head
Lead compounds
Pharmacokinetics
Structure-Activity Relationship
Hydrophobic and Hydrophilic Interactions
Skeleton
Scaffolds
Carrier Proteins
Proteins
Substitution reactions
indole
Derivatives
Glucose

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Mahindroo, N., Huang, C. F., Peng, Y. H., Wang, C. C., Liao, C. C., Lien, T. W., ... 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

Novel indole-based peroxisome proliferator-activated receptor agonists : Design, SAR, structural biology, and biological activities. / Mahindroo, Neeraj; Huang, Chien Fu; Peng, Yi Huei; Wang, Chiung Chiu; Liao, Chun Chen; Lien, Tzu Wen; Chittimalla, Santhosh Kumar; Huang, Wei Jan; Chai, Chia Hua; Prakash, Ekambaranellore; Chen, Ching Ping; Hsu, Tsu An; Peng, Cheng Hung; Lu, I. Lin; Lee, Ling Hui; Chang, Yi Wei; Chen, Wei Cheng; Chou, Yu Chen; Chen, Chiung Tong; Goparaju, Chandra M V; Chen, Yuan Shou; Lan, Shih Jung; Yu, Ming Chen; Chen, Xin; Chao, Yu Sheng; Wu, Su Ying; Hsieh, Hsing Pang.

In: Journal of Medicinal Chemistry, Vol. 48, No. 26, 29.12.2005, p. 8194-8208.

Research output: Contribution to journalArticle

Mahindroo, N, Huang, CF, Peng, YH, Wang, CC, Liao, CC, Lien, TW, Chittimalla, SK, Huang, WJ, Chai, CH, Prakash, E, Chen, CP, Hsu, TA, Peng, CH, Lu, IL, Lee, LH, Chang, YW, Chen, WC, Chou, YC, Chen, CT, Goparaju, CMV, Chen, YS, Lan, SJ, Yu, MC, Chen, X, Chao, YS, Wu, SY & Hsieh, HP 2005, 'Novel indole-based peroxisome proliferator-activated receptor agonists: Design, SAR, structural biology, and biological activities', Journal of Medicinal Chemistry, vol. 48, no. 26, pp. 8194-8208. https://doi.org/10.1021/jm0506930
Mahindroo, Neeraj ; Huang, Chien Fu ; Peng, Yi Huei ; Wang, Chiung Chiu ; Liao, Chun Chen ; Lien, Tzu Wen ; Chittimalla, Santhosh Kumar ; Huang, Wei Jan ; Chai, Chia Hua ; Prakash, Ekambaranellore ; Chen, Ching Ping ; Hsu, Tsu An ; Peng, Cheng Hung ; Lu, I. Lin ; Lee, Ling Hui ; Chang, Yi Wei ; Chen, Wei Cheng ; Chou, Yu Chen ; Chen, Chiung Tong ; Goparaju, Chandra M V ; Chen, Yuan Shou ; Lan, Shih Jung ; Yu, Ming Chen ; Chen, Xin ; Chao, Yu Sheng ; Wu, Su Ying ; Hsieh, Hsing Pang. / Novel indole-based peroxisome proliferator-activated receptor agonists : Design, SAR, structural biology, and biological activities. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 26. pp. 8194-8208.
@article{43a4ca458ba341dc819e212f76f83869,
title = "Novel indole-based peroxisome proliferator-activated receptor agonists: Design, SAR, structural biology, and biological activities",
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.",
author = "Neeraj Mahindroo and Huang, {Chien Fu} and Peng, {Yi Huei} and Wang, {Chiung Chiu} and Liao, {Chun Chen} and Lien, {Tzu Wen} and Chittimalla, {Santhosh Kumar} and Huang, {Wei Jan} and Chai, {Chia Hua} and Ekambaranellore Prakash and Chen, {Ching Ping} and Hsu, {Tsu An} and Peng, {Cheng Hung} and Lu, {I. Lin} and Lee, {Ling Hui} and Chang, {Yi Wei} and Chen, {Wei Cheng} and Chou, {Yu Chen} and Chen, {Chiung Tong} and Goparaju, {Chandra M V} and Chen, {Yuan Shou} and Lan, {Shih Jung} and Yu, {Ming Chen} and Xin Chen and Chao, {Yu Sheng} and Wu, {Su Ying} and Hsieh, {Hsing Pang}",
year = "2005",
month = "12",
day = "29",
doi = "10.1021/jm0506930",
language = "English",
volume = "48",
pages = "8194--8208",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "26",

}

TY - JOUR

T1 - Novel indole-based peroxisome proliferator-activated receptor agonists

T2 - Design, SAR, structural biology, and biological activities

AU - Mahindroo, Neeraj

AU - Huang, Chien Fu

AU - Peng, Yi Huei

AU - Wang, Chiung Chiu

AU - Liao, Chun Chen

AU - Lien, Tzu Wen

AU - Chittimalla, Santhosh Kumar

AU - Huang, Wei Jan

AU - Chai, Chia Hua

AU - Prakash, Ekambaranellore

AU - Chen, Ching Ping

AU - Hsu, Tsu An

AU - Peng, Cheng Hung

AU - Lu, I. Lin

AU - Lee, Ling Hui

AU - Chang, Yi Wei

AU - Chen, Wei Cheng

AU - Chou, Yu Chen

AU - Chen, Chiung Tong

AU - Goparaju, Chandra M V

AU - Chen, Yuan Shou

AU - Lan, Shih Jung

AU - Yu, Ming Chen

AU - Chen, Xin

AU - Chao, Yu Sheng

AU - Wu, Su Ying

AU - Hsieh, Hsing Pang

PY - 2005/12/29

Y1 - 2005/12/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=29744432852&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29744432852&partnerID=8YFLogxK

U2 - 10.1021/jm0506930

DO - 10.1021/jm0506930

M3 - Article

C2 - 16366601

AN - SCOPUS:29744432852

VL - 48

SP - 8194

EP - 8208

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 26

ER -