title: 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).
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.
authors.affiliation: Department of Medicinal Chemistry, Myrexis, Inc., Salt Lake City, Utah 84108, USA. jeffrey.lockman@myrexis.com
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lockman
authors.forename: Brett R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Zigar
authors.forename: Weston R
authors.initials: WR
authors.lastname: Judd
authors.forename: Paul M
authors.initials: PM
authors.lastname: Slattum
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Gao
authors.forename: Kirill
authors.initials: K
authors.lastname: Ostanin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.forename: Rena
authors.initials: R
authors.lastname: McKinnon
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Terry-Lorenzo
authors.forename: Tracey C
authors.initials: TC
authors.lastname: Fleischer
authors.forename: J Jay
authors.initials: JJ
authors.lastname: Boniface
authors.forename: Mark
authors.initials: M
authors.lastname: Shenderovich
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C403613:CB 30865; D011799:Quinazolines; D054409:Nicotinamide Phosphoribosyltransferase