Progettazione e sintesi di nuovi antagonisti CB1 a struttura 5-eteroaril-1-(2',4'-diclorofenil)-4-metil-1H-pirazol-3-carbossammidica quali potenziali candidati per il trattamento dell'obesità

My research work was centered on the design and synthesis of novel 5-heteroaryl-pirazoles CB₁ antagonists, exibiting high tPSA values in attempt to reduce the BBB permeation¹. It is now well accepted that bioisosteric replacement of aryl substituent on pyrazole C-5 of Rimonabant with a conveniently appended 2-thienyl moiety leads to highly potent CB₁ receptor antagonists². <br>Attempting to improve the CB₁ selectivity inside this class, we have synthesized a series of analogue compounds replacing the 5-(5-halo-2-thienyl) with a 5-(5-aryl-2-thienyl) moiety. Within this new class, the 5-(2,2'-bithiophen-5-yl)-1-(2,4-dichlorophenyl)-4-methyl-<i>N</i>-(piperidin-1-yl)-1<i>H</i>pirazole- 3-carboxamide showed the most promising pharmacological profile and was chosen for a chronic treatment in C57BL/6N Diet-Induced Obesity (DIO) mice, highlighting a Rimonbant-like anti-obesity activity. The replacement of pyrazole 5-(3-chloro-1-phenyl) substituent of Rimonabant with a conveniently appended pyridinyl moiety leaded to an interesting new class of potential CB₁ receptor antagonists exhibiting low lipophilicity and high tPSA values. The synthesis of novel 5-(5-bromo-1<i>H</i>-pyrrol-2-yl)-1-(2,4-dichlorophenil)-4-methyl-1<i>H</i>-pirazole-3-carboxamides was also attempted but not achieved.</br>