title: Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
abstract: Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. duan@bms.com
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lu
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Asakawa
authors.forename: James E
authors.initials: JE
authors.lastname: Sheppeck
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: William
authors.initials: W
authors.lastname: Pitts
authors.forename: Soong-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001463:Barbiturates; D001549:Benzamides; D006877:Hydroxamic Acids; C519012:N-(4-(methanesulfonylpiperazin-1-yl)-2,4,6-trioxopyrimidin-4-ylmethyl)-4-((2-methylquinolin-4-yl)methoxy)benzamide; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein