[Epub ahead of print]
Discovery of 1-(2,4-Dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-1H-pyrazole-3-carboxamide as a Novel Peripherally Restricted Cannabinoid-1 Receptor Antagonist with Significant Weight-Loss Efficacy in Diet-Induced Obese (DIO) Mice.
Chang CP, Wu CH, Song JS, Chou MC, Wong YC, Lin Y, Yeh TK, Sadani AA, Ou MH, Chen KH, Chen PH, Kuo PC, Tseng CT, Chang KH, Tseng SL, Chao YS, Hung MS, Shia KS.
Abstract
After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 (B/P = 1/33) with a different electronegative group. Especially, when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Å2, a threshold considered to possess a low probability to cross BBB, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound 4 displays also clean 163 off-target profiles and is currently under development for treating obesity and the related metabolic syndrome.
- PMID:
- 24224693
- [PubMed – as supplied by publisher]
