Gabriele Murineddu, Battistina Asproni, Stefania Ruiu, Francesco Deligia, Matteo Falzoi, Amedeo Pau, Brian F Thomas, Yanan Zhang, Gérard A Pinna, Luca Pani, Paolo Lazzari
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引用次数: 12
摘要
为了寻找新的选择性CB2配体，详细介绍了高效原型5-(4-氯-3-甲基苯基)-1-(4-甲基苄基)- n-芬基- 1h -吡唑-3-羧基酰胺1和1-(2,4-二氯苯基)-6-甲基- n-(胡椒碱-1-基)-1,4-二氢茚- [1,2-c]吡唑-3-羧基酰胺2的新型1,4-二氢茚[1,2-c]吡唑复合物的合成和初步生物学评价。我们推测，在2的三环核心中引入1活性所必需的药效元件可能会进一步提高CB2配体的受体选择性和生物活性。在这些化合物中，6-氯-7-甲基-1-(2,4-二氯苯基)- n -芬基-1,4-二氢茚[1,2-c]吡唑-3-羧酰胺(22)对大麻素CB2R具有低两位数纳米摩尔亲和力，并保持高水平的cb2选择性。
Tricyclic Pyrazoles. Part 5. Novel 1,4-Dihydroindeno[1,2-c]pyrazole CB2 Ligands Using Molecular Hybridization Based on Scaffold Hopping.
In search of new selective CB2 ligands, the synthesis and preliminary biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazole hybrids of the highly potent prototypicals 5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-fenchyl-1H-pyrazole-3-carboxamide 1 and 1-(2,4-dichlorophenyl)-6-methyl-N-(piperidin-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide 2 are detailed.We postulated that the introduction of those pharmacophoric elements essential for activity of 1 in the tricyclic core of 2 might provide CB2 ligands with further improved receptor selectivity and biological activity. Among the compounds, 6-chloro-7-methyl-1-(2,4-dichlorophenyl)-N-fenchyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide (22) exhibited low two digit nanomolar affinity for the cannabinoid CB2R and maintained a high level of CB2-selectivity.
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