Pira, Marilena (2014) 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. Doctoral Thesis.
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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.
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-N-(piperidin-1-yl)-1Hpirazole-
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-1H-pyrrol-2-yl)-1-(2,4-dichlorophenil)-4-methyl-1H-pirazole-3-carboxamides was also attempted but not achieved.
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