Murineddu Gabriele, Asproni Battistina, Ruiu Stefania, Deligia Francesco, Falzoi Matteo, Pau Amedeo, Thomas Brian F, Zhang Yanan, Pinna Gérard A, Pani Luca, Lazzari Paolo
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
Open Med Chem J. 2012;6:1-14. doi: 10.2174/1874104501206010001. Epub 2012 May 17.
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.
为了寻找新的选择性CB2配体，我们详细介绍了新型1,4-二氢茚并[1,2-c]吡唑杂合物的合成及初步生物学评价，这些杂合物基于高效原型化合物5-(4-氯-3-甲基苯基)-1-(4-甲基苄基)-N-葑基-1H-吡唑-3-甲酰胺1和1-(2,4-二氯苯基)-6-甲基-N-(哌啶-1-基)-1,4-二氢茚并[1,2-c]吡唑-3-甲酰胺2。我们推测，将对1的活性至关重要的那些药效基团引入到2的三环核心中，可能会提供具有进一步改善的受体选择性和生物学活性的CB2配体。在这些化合物中，6-氯-7-甲基-1-(2,4-二氯苯基)-N-葑基-1,4-二氢茚并[1,2-c]吡唑-3-甲酰胺(22)对大麻素CB2R表现出低两位数纳摩尔亲和力，并保持了高水平的CB2选择性。
