1362147-37-2Relevant academic research and scientific papers
Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5- carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
Zheng, Xiaozhang,Bair, Kenneth W.,Bauer, Paul,Baumeister, Timm,Bowman, Krista K.,Buckmelter, Alexandre J.,Caligiuri, Maureen,Clodfelter, Karl H.,Feng, Yezhen,Han, Bingsong,Ho, Yen-Ching,Kley, Nikolai,Li, Hong,Liang, Xiaorong,Liederer, Bianca M.,Lin, Jian,Ly, Justin,O'Brien, Thomas,Oeh, Jason,Oh, Angela,Reynolds, Dominic J.,Sampath, Deepak,Sharma, Geeta,Skelton, Nicholas,Smith, Chase C.,Tremayne, Jarrod,Wang, Leslie,Wang, Weiru,Wang, Zhongguo,Wu, Hongxing,Wu, Jiansheng,Xiao, Yang,Yang, Guangxing,Yuen, Po-Wai,Zak, Mark,Dragovich, Peter S.
, p. 5488 - 5497 (2013/10/01)
Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities a
Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors
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.
, p. 6413 - 6433 (2013/09/23)
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 IC 50 = 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.
