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

  • J Med Chem. 2010 Dec 23;53(24):8734-46. doi: 10.1021/jm101145b.
Jeffrey W Lockman  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Myrexis, Inc., Salt Lake City, Utah 84108, USA. [email protected]
PMID: 21080724 DOI: 10.1021/jm101145b
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.