Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity.
Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity.
复制标题
DOI：
10.1021/jm201731z
复制
发表时间：
2012-03-22
影响因子：
7.3
通讯作者：
Maitra, Rangan
中科院分区：
文献类型：
--
作者：
Fulp, Alan;Bortoff, Katherine;Seltzman, Herbert;Zhang, Yanan;Mathews, James;Snyder, Rodney;Fennell, Tim;Maitra, Rangan
大麻素受体1（CB1）的拮抗剂具有治疗多种疾病的潜力，如肥胖症，肝病和糖尿病。最近，由于利莫那班（第一个临床批准的CB1反向激动剂）观察到的不良中枢神经系统（CNS）相关副作用，几种CB1拮抗剂的开发被停止。然而，最近的研究表明，调节外周表达的CB1与CNS保留化合物是一个可行的策略来治疗几个重要的疾病。我们旨在合理设计外周限制性CB1拮抗剂的努力已经导致在临床前体外和体内模型中具有有限血脑屏障（BBB）渗透性和CNS暴露的化合物。通常，具有高拓扑极性表面积（TPSAs）的化合物不会被动地穿过BBB。鉴定了具有比利莫那班更高的TPSA（利莫那班TPSA = 50）和具有有限CNS渗透的优异功能活性的化合物。这些化合物将作为进一步优化的模板。
Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease and diabetes. Recently, development of several CB1 antagonists was halted due to adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.
登录
查看更多内容
影响因子：
3.2
作者：
Garberg, P;Ball, M;Österberg, T
通讯作者：
Österberg, T
影响因子：
3.9
作者：
Doran, A;Obach, RS;Zhang, CH
通讯作者：
Zhang, CH
影响因子：
1.8
作者：
Seltzman, HH;Carroll, FI;Burch, DF
通讯作者：
Burch, DF
影响因子：
2.7
作者：
LoVerme J;Duranti A;Tontini A;Spadoni G;Mor M;Rivara S;Stella N;Xu C;Tarzia G;Piomelli D
通讯作者：
Piomelli D
影响因子：
4.8
作者：
Bouaboula, M;Perrachon, S;Casellas, P
通讯作者：
Casellas, P