- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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- Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
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Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.
- Dragovich, Peter S.,Bair, Kenneth W.,Baumeister, Timm,Ho, Yen-Ching,Liederer, Bianca M.,Liu, Xiongcai,Liu, Yongbo,O'Brien, Thomas,Oeh, Jason,Sampath, Deepak,Skelton, Nicholas,Wang, Leslie,Wang, Weiru,Wu, Hongxing,Xiao, Yang,Yuen, Po-Wai,Zak, Mark,Zhang, Lei,Zheng, Xiaozhang
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p. 4875 - 4885
(2013/09/02)
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