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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Crystallography, X-Ray
  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology*
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Phenotype
  • Structure-Activity Relationship

Substances

  • Amides
  • Cyclopropanes
  • Cytokines
  • Enzyme Inhibitors
  • N-cyclopropyl adenosine-5'-carboxamide
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • Adenosine