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J Med Chem ; 53(24): 8734-46, 2010 Dec 23.
Article in English | MEDLINE | ID: mdl-21080724

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Quinazolines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Models, Molecular , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity Relationship
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