title: Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships.
abstract: New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. james.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: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lu
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Karl D
authors.initials: KD
authors.lastname: Hardman
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D006877:Hydroxamic Acids; C468787:IK 682; D007769:Lactams; D011480:Protease Inhibitors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat