title: Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors: Part I--discovery of two binding modes.
abstract: Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-alpha converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure-activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1'-S3' binding pockets, whereas mode B resides in the nonprime binding sites.
authors.affiliation: Department of Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Zhaoning.Zhu@spcorp.com
authors.forename: Zhaoning
authors.initials: Z
authors.lastname: Zhu
authors.forename: Robert
authors.initials: R
authors.lastname: Mazzola
authors.forename: Lisa
authors.initials: L
authors.lastname: Sinning
authors.forename: Brian
authors.initials: B
authors.lastname: McKittrick
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Niu
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: Richard
authors.initials: R
authors.lastname: Ingram
authors.forename: Brian M
authors.initials: BM
authors.lastname: Beyer
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000072198:ADAM17 Protein; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein