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 journalArticle

23 Citations (Scopus)

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

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Nicotinamide Phosphoribosyltransferase
Cytotoxins
CB 30865
benzamide

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Lockman, Jeffrey W. ; Murphy, Brett R. ; Zigar, Daniel F. ; Judd, Weston R. ; Slattum, Paul M. ; Gao, Zhong Hua ; Ostanin, Kirill ; Green, Jeremy ; McKinnon, Rena ; Terry-Lorenzo, Ryan T. ; Fleischer, Tracey C. ; Boniface, J. Jay ; Shenderovich, Mark ; Willardsen, J. Adam. / 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). In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 24. pp. 8734-8746.
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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.",
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Lockman, JW, Murphy, BR, Zigar, DF, Judd, WR, Slattum, PM, Gao, ZH, Ostanin, K, Green, J, McKinnon, R, Terry-Lorenzo, RT, Fleischer, TC, Boniface, JJ, Shenderovich, M & Willardsen, JA 2010, '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)', Journal of Medicinal Chemistry, vol. 53, no. 24, pp. 8734-8746. https://doi.org/10.1021/jm101145b

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

In: Journal of Medicinal Chemistry, Vol. 53, No. 24, 23.12.2010, p. 8734-8746.

Research output: Contribution to journalArticle

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T1 - 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)

AU - Lockman, Jeffrey W.

AU - Murphy, Brett R.

AU - Zigar, Daniel F.

AU - Judd, Weston R.

AU - Slattum, Paul M.

AU - Gao, Zhong Hua

AU - Ostanin, Kirill

AU - Green, Jeremy

AU - McKinnon, Rena

AU - Terry-Lorenzo, Ryan T.

AU - Fleischer, Tracey C.

AU - Boniface, J. Jay

AU - Shenderovich, Mark

AU - Willardsen, J. Adam

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N2 - 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.

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