Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3 H -quinazolin-6-yl)methylprop-2- ynylamino]- N -(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt)

Jeffrey W. Lockman, Brett R. Murphy, Daniel F. Zigar, Weston R. Judd, Paul M. Slattum, Zhong Hua Gao, Kirill Ostanin, Jeremy Green, Rena McKinnon, Ryan T. Terry-Lorenzo, Tracey C. Fleischer, J. Jay Boniface, Mark Shenderovich, J. Adam Willardsen

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino] -N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C2 of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.

Original languageEnglish (US)
Pages (from-to)8734-8746
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number24
DOIs
StatePublished - Dec 23 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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