Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
| Autor: | Xiaorong Liang, Weiru Wang, Zhongguo Wang, Alexandre J. Buckmelter, Bianca M. Liederer, Maureen Caligiuri, Nicholas J. Skelton, Karl H. Clodfelter, Yang Xiao, Leslie Wang, Timm Baumeister, Thomas O'Brien, Peter S. Dragovich, Nikolai Kley, Mark Zak, Jiansheng Wu, Xiaozhang Zheng, Yezhen Feng, Angela Oh, Hongxing Wu, Guangxing Yang, Kenneth W. Bair, Geeta Sharma, Dominic J. Reynolds, Krista K. Bowman, Chase C. Smith, Jian Lin, Yuen Po-Wai, Jason Oeh, Hong Li, Jarrod Tremayne, Deepak Sampath, Paul Bauer, Yen-Ching Ho, Bingsong Han, Justin Ly |
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| Rok vydání: | 2013 |
| Předmět: |
Niacinamide
Pyridines Clinical Biochemistry Transplantation Heterologous Nicotinamide phosphoribosyltransferase Carboxylic Acids Pharmaceutical Science Mice Nude Crystallography X-Ray Biochemistry Retina chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery Structure–activity relationship Animals Humans Sulfones Enzyme Inhibitors Nicotinamide Phosphoribosyltransferase Molecular Biology Cell Proliferation chemistry.chemical_classification Binding Sites Cell growth Organic Chemistry Haplorhini NAD Amides In vitro Protein Structure Tertiary Rats Enzyme chemistry Cell culture Molecular Medicine Cytokines Pyrazoles Female NAD+ kinase Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 23(20) |
| ISSN: | 1464-3405 |
| Popis: | 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 against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained. |
| Databáze: | OpenAIRE |
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