Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

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• 作者：Xiaozhang Zheng ; Paul Bauer ; Timm Baumeister ; Alexandre J. Buckmelter ; Maureen Caligiuri ; Karl H. Clodfelter ; Bingsong Han ; Yen-Ching Ho ; Nikolai Kley ; Jian Lin ; Dominic J. Reynolds ; Geeta Sharma ; Chase C. Smith ; Zhongguo Wang ; Peter S. Dragovich ; Janet Gunzner-Toste ; Bianca M. Liederer ; Justin Ly ; Thomas O鈥橞rien ; Angela Oh ; Leslie Wang ; Weiru Wang ; Yang Xiao ; Mark Zak ; Guiling Zhao ; Po-wai Yuen ; Kenneth W. Bair
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6413-6433
• 全文大小：834K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC₅₀ = 9.0 nM, A2780 cell proliferation IC₅₀ = 10 nM). The Nampt鈥?b>7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC₅₀ <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.