Bioisosteric replacements of the pyrazole moiety of rimonabant:: Synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists
Bioisosteric replacements of the pyrazole moiety of rimonabant:: Synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists
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DOI：
10.1021/jm040843r
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发表时间：
2005-03-24
影响因子：
7.3
通讯作者：
Kruse, CG
中科院分区：
文献类型：
--
作者：
Lange, JHM;van Stuivenberg, HH;Kruse, CG
基于强效CB受体拮抗剂利莫那班（SR 141716 A，1）中存在的1，5-二芳基吡唑基序，设计了一系列噻唑、三唑和咪唑类化合物作为生物电子等排体。合成了许多目标化合物，并在大麻素（hCB（1）和hCB（2））受体测定中进行了评价。噻唑类、三唑类和咪唑类引起体外CB拮抗活性，并且通常表现出相当大的CB 1与CB 2受体亚型选择性，从而证明是原始二芳基吡唑类的大麻素生物电子等排体。咪唑系列中的一些关键代表在CB激动剂诱导的低血压模型和CB激动剂诱导的低温模型中口服给药后显示出有效的体内药理活性。分子模拟研究表明，关键化合物62和利莫那班之间存在密切的三维结构重叠。构效关系（SAR）的研究表明，在咪唑和吡唑系列的生物学结果之间的密切相关性。
Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB, receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro CB, antagonistic activities and in general exhibited considerable CB1 vs CB2 receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.