Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
2013; American Chemical Society; Volume: 56; Issue: 16 Linguagem: Inglês
10.1021/jm4008664
ISSN1520-4804
AutoresXiaozhang 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 Q. Ly, Thomas O’Brien, Angela Oh, Leslie Wang, Weiru Wang, Yang Xiao, Mark Zak, Gui‐Ling Zhao, Po‐wai Yuen, Kenneth W. Bair,
Tópico(s)HIV/AIDS drug development and treatment
ResumoCrystal 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.
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