Chemical and Biological Investigation of Cyclopropyl Containing Diaryl-pyrazole-3-carboxamides as Novel and Potent Cannabinoid Type 1 Receptor Antagonists

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• 作者：Gyrgy Szab ; Balzs Varga ; Dra Pyer-Lengyel ; Attila Szemz ; Pter Erdlyi ; Krisztina Vukics ; Judit Szikra ; va Hegyi ; Mnika Vastag ; Bla Kiss ; Judit Laszy ; Istvn Gyertyn ; Jnos Fischer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4329-4337
• 全文大小：895K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities. Thorough structure−activity relationship (SAR) studies to optimize the pyrazole substituents led to several novel CB1 antagonists with K_i ≤ 5 nM and with acceptable metabolic stability with human liver microsomes. Among these analogues, we identified 5-(4-cyclopropylphenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-pyrrolidin-1-yl-1H-pyrazole-3-carboxamide (11r), which exhibited a favorable pharmacological profile with outstanding efficacy in reducing serum lipid parameters of metabolic syndrome compared to clinical references.