Design of a New Histamine H3 Receptor Antagonist Chemotype: (3aR,6aR)-5-Alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, Synthesis, and Structure−Activity Relationsh

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• 作者：Chen Zhao ; Minghua Sun ; Youssef L. Bennani ; Thomas R. Miller ; David G. Witte ; Timothy A. Esbenshade ; Jill Wetter ; Kennan C. Marsh ; Arthur A. Hancock ; Jorge D. Brioni ; Marlon D. Cowart
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4640-4649
• 全文大小：931K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

A new histamine H₃ receptor (H₃R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H₃R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H₃R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H₃R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H₃ K_i of 0.54 nM, rat H₃ K_i of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t_1/2 of 2.4 h).