title: Conversion of potent MMP inhibitors into selective TACE inhibitors.
abstract: Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.forename: Bryan W
authors.initials: BW
authors.lastname: King
authors.forename: John L
authors.initials: JL
authors.lastname: Gilmore
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein