Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities.
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.
Mahindroo
Neeraj
N
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
Huang
Chien-Fu
CF
Peng
Yi-Huei
YH
Wang
Chiung-Chiu
CC
Liao
Chun-Chen
CC
Lien
Tzu-Wen
TW
Chittimalla
Santhosh Kumar
SK
Huang
Wei-Jan
WJ
Chai
Chia-Hua
CH
Prakash
Ekambaranellore
E
Chen
Ching-Ping
CP
Hsu
Tsu-An
TA
Peng
Cheng-Hung
CH
Lu
I-Lin
IL
Lee
Ling-Hui
LH
Chang
Yi-Wei
YW
Chen
Wei-Cheng
WC
Chou
Yu-Chen
YC
Chen
Chiung-Tong
CT
Goparaju
Chandra M V
CM
Chen
Yuan-Shou
YS
Lan
Shih-Jung
SJ
Yu
Ming-Chen
MC
Chen
Xin
X
Chao
Yu-Sheng
YS
Wu
Su-Ying
SY
Hsieh
Hsing-Pang
HP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003460:Crystallization; D003461:Crystallography; D003847:Deoxyglucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007211:Indoles; D007328:Insulin; D007555:Isoxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D003907:Dexamethasone; D003847:Deoxyglucose; D015056:1-Methyl-3-isobutylxanthine