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Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Feb 01; Vol. 28 (3), pp. 365-370. Date of Electronic Publication: 2017 Dec 18. - Publication Year :
- 2018
-
Abstract
- Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adenosine analogs & derivatives
Amides chemical synthesis
Amides chemistry
Crystallography, X-Ray
Cyclopropanes chemical synthesis
Cyclopropanes chemistry
Cytokines metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Humans
Molecular Docking Simulation
Molecular Structure
Nicotinamide Phosphoribosyltransferase metabolism
Phenotype
Structure-Activity Relationship
Amides pharmacology
Cyclopropanes pharmacology
Cytokines antagonists & inhibitors
Drug Design
Enzyme Inhibitors pharmacology
Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 29275937
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.12.037