Back to Search
Start Over
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 [Bioorg Med Chem Lett] 2013 Sep 01; Vol. 23 (17), pp. 4875-85. Date of Electronic Publication: 2013 Jul 06. - Publication Year :
- 2013
-
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 = 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.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Cell Line, Tumor
Cytokines metabolism
Humans
Mice
Mice, Nude
Models, Molecular
Neoplasms drug therapy
Neoplasms enzymology
Nicotinamide Phosphoribosyltransferase metabolism
Pyridines pharmacokinetics
Pyridines pharmacology
Structure-Activity Relationship
Urea pharmacokinetics
Urea pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
Cytokines antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
Pyridines chemistry
Pyridines therapeutic use
Urea chemistry
Urea therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 23
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23899614
- Full Text :
- https://doi.org/10.1016/j.bmcl.2013.06.090