71311-86-9Relevant articles and documents
Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2
Liu, Qiufeng,Huang, Fubao,Yuan, Xiaojing,Wang, Kai,Zou, Yi,Shen, Jianhua,Xu, Yechun
supporting information, p. 10231 - 10244 (2018/01/10)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity
Taygerly, Joshua P.,McGee, Lawrence R.,Rubenstein, Steven M.,Houze, Jonathan B.,Cushing, Timothy D.,Li, Yang,Motani, Alykhan,Chen, Jin-Long,Frankmoelle, Walter,Ye, Guosen,Learned, Marc R.,Jaen, Juan,Miao, Shichang,Timmermans, Pieter B.,Thoolen, Martin,Kearney, Patrick,Flygare, John,Beckmann, Holger,Weiszmann, Jennifer,Lindstrom, Michelle,Walker, Nigel,Liu, Jinsong,Biermann, Donna,Wang, Zhulun,Hagiwara, Atsushi,Iida, Tetsuya,Aramaki, Hisateru,Kitao, Yuki,Shinkai, Hisashi,Furukawa, Noboru,Nishiu, Jun,Nakamura, Motonao
, p. 979 - 992 (2013/03/28)
PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
Therapeutic modulation of PPARgamma activity
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Page/Page column 34, (2010/02/14)
Modulators of PPARγ activity are used in methods of treating and/or preventing conditions such as osteoporosis, Alzheimer's disease, psoriasis and acne, and cancer.
