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 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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Mahindroo
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Huang
authors.forename: Yi-Huei
authors.initials: YH
authors.lastname: Peng
authors.forename: Chiung-Chiu
authors.initials: CC
authors.lastname: Wang
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Liao
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Lien
authors.forename: Santhosh Kumar
authors.initials: SK
authors.lastname: Chittimalla
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Chai
authors.forename: Ekambaranellore
authors.initials: E
authors.lastname: Prakash
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Tsu-An
authors.initials: TA
authors.lastname: Hsu
authors.forename: Cheng-Hung
authors.initials: CH
authors.lastname: Peng
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Lu
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Lee
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chang
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Chen
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Chou
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Chandra M V
authors.initials: CM
authors.lastname: Goparaju
authors.forename: Yuan-Shou
authors.initials: YS
authors.lastname: Chen
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Lan
authors.forename: Ming-Chen
authors.initials: MC
authors.lastname: Yu
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: 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
chemical_list: D007211:Indoles; D007328:Insulin; D007555:Isoxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D003907:Dexamethasone; D003847:Deoxyglucose; D015056:1-Methyl-3-isobutylxanthine