title: MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres.
abstract: Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas_e_barta@yahoo.com
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Barta
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Becker
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Bedell
authors.forename: Alan M
authors.initials: AM
authors.lastname: Easton
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hockerman
authors.forename: James
authors.initials: J
authors.lastname: Kiefer
authors.forename: Grace E
authors.initials: GE
authors.lastname: Munie
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Mathis
authors.forename: Madeleine H
authors.initials: MH
authors.lastname: Li
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Rico
authors.forename: Clara I
authors.initials: CI
authors.lastname: Villamil
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Williams
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013450:Sulfones; D053509:Matrix Metalloproteinase 13