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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).
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Sep2013, Vol. 23 Issue 17, p4875-4885. 11p. - Publication Year :
- 2013
-
Abstract
- Abstract: 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 =11nM; PC-3 antiproliferative IC50 =36nM), 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 =7nM) in complex with the NAMPT protein was also determined. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 23
- Issue :
- 17
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 89606237
- Full Text :
- https://doi.org/10.1016/j.bmcl.2013.06.090