Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
| Autor: | Bianca M. Liederer, Xiaozhang Zheng, Kenneth W. Bair, Yen-Ching Ho, Timm Baumeister, Nicholas J. Skelton, Leslie Wang, Weiru Wang, Thomas O'Brien, Lei Zhang, Jason Oeh, Yuen Po-Wai, Yongbo Liu, Peter S. Dragovich, Deepak Sampath, Yang Xiao, Xiongcai Liu, Mark Zak, Hongxing Wu |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Pyridines Stereochemistry Clinical Biochemistry Nicotinamide phosphoribosyltransferase Mice Nude Pharmaceutical Science Antineoplastic Agents Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Mouse xenograft Cell Line Tumor Neoplasms Drug Discovery Aqueous solubility Pyridine Animals Humans Urea Solubility Nicotinamide Phosphoribosyltransferase Molecular Biology IC50 Chemistry Organic Chemistry Cytokines Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:4875-4885 |
| ISSN: | 0960-894X |
| Popis: | 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 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined. |
| Databáze: | OpenAIRE |
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