Structure-Based Identification of Ureas as Novel 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 ; Angela Oh ; Weiru Wang ; Mark Zak ; Janet Gunzner-Toste ; Guiling Zhao ; Po-wai Yuen ; Kenneth W. Bair
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：4921-4937
• 全文大小：897K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC₅₀ = 0.007 渭M; A2780 IC₅₀ = 0.032 渭M). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).