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Bioorg Med Chem Lett. 2018 Feb 1;28(3):365-370. doi: 10.1016/j.bmcl.2017.12.037. Epub 2017 Dec 18.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Author information

1
Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA. Electronic address: daniel.palacios@novartis.com.
2
Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA.
3
Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA.
4
PK Sciences, Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

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.

KEYWORDS:

Cyclopropane; In silico screen; NAMPT; Nicotinamide phosphoribosyltransferase; Structure based drug design

PMID:
29275937
DOI:
10.1016/j.bmcl.2017.12.037
[Indexed for MEDLINE]

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