Discovery of 1-(2,4-Dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a Potential Peripheral Cannabinoid-1 Receptor Inverse Agonist

摘要

Cannabinoid-1 receptor (CB1R) is one of the most abundant neuroculatory receptors in the brain, and it is involved in regulating feeding and appetite. In addition to expression in brain, this receptor is also found in the peripheral organs, such as adipose tissues, muscle, and liver. In sharp contrast, the structurally closely related cannabinoid-2 receptor (CB2R) is expressed almost exclusively in the immune system and is primarily involved in immune regulation and neurodegenera-tion. The therapeutic potential of CB1R antagonists has been extensively reviewed,141 and at least one compound (1; also called rimonabant or SR141716A) has shown clinical evidence of weight reducing action. However, after its launch in 2006, it was subsequently withdrawn (2008) in Europe due to severe psychiatric effects including depression, anxiety and stress disorders. Currently, only two drugs, orlistat and sibutramine, are available for the long-term treatment of obesity; however, both have met with moderate success because of their limited weight-loss efficacy and many accompanying adverse effects, including high blood pressure and flatulence.