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

• Published in: Journal of medicinal chemistry Vol. 56; no. 16; pp. 6413 - 6433
• Main Authors: Zheng, Xiaozhang, Bauer, Paul, Baumeister, Timm, Buckmelter, Alexandre J, Caligiuri, Maureen, Clodfelter, Karl H, Han, Bingsong, Ho, Yen-Ching, Kley, Nikolai, Lin, Jian, Reynolds, Dominic J, Sharma, Geeta, Smith, Chase C, Wang, Zhongguo, Dragovich, Peter S, Gunzner-Toste, Janet, Liederer, Bianca M, Ly, Justin, O’Brien, Thomas, Oh, Angela, Wang, Leslie, Wang, Weiru, Xiao, Yang, Zak, Mark, Zhao, Guiling, Yuen, Po-wai, Bair, Kenneth W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-08-2013
• Subjects: Animals; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4008664

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–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.