Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure鈥揂ctivity Relationship

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• 作者：Mette K. Christensen ; Kamille D. Erichsen ; Uffe H. Olesen ; Jette Tj酶rnelund ; Peter Fristrup ; Annemette Thougaard ; S酶ren Jensby Nielsen ; Maxwell Sehested ; Peter B. Jensen ; Einars Loza ; Ivars Kalvinsh ; Antje Garten ; Wieland Kiess ; Fredrik Bj枚rkling
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9071-9088
• 全文大小：908K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure鈥揳ctivity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC₅₀ 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm³), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1鈥?. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.