设计、合成及功能化四氢-β-咔啉衍生物的构效关系作为新型 PDE5 抑制剂。
Design, synthesis and structure-activity relationship of functionalized tetrahydro-β-carboline derivatives as novel PDE5 inhibitors.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
出版信息
Arch Pharm (Weinheim). 2011 Mar;344(3):149-57. doi: 10.1002/ardp.201000236. Epub 2010 Dec 22.
Abstract
Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50) = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.
摘要
以他达拉非为模板，我们合成了一系列的四氢-β-咔啉衍生物，并将其鉴定为新型强效和选择性 PDE5 抑制剂。将他达拉非 6 位的 3,4-亚甲二氧基苯基替换，同时延长 N2-甲基取代基，并调整两个手性碳原子的立体化学方面，得到了化合物 XXI，这是一种高效的 PDE5 抑制剂（IC50=3 nM）。化合物 XXI 对 PDE5 的选择性也高于 PDE3B、PDE4B 和 PDE11A，分别以 cAMP 和 cGMP 为底物时，对 PDE5 的选择性指数为 52 和 235，而对 PDE11 的选择性指数分别为 52 和 235。
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