title: The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis.
abstract: Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.
authors.affiliation: Respiratory and Inflammation Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK. chris.desavi2@astrazeneca.com
authors.forename: Chris
authors.initials: C
authors.lastname: De Savi
authors.forename: Andrew
authors.initials: A
authors.lastname: Pape
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.forename: Peter D
authors.initials: PD
authors.lastname: Smith
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Mark
authors.initials: M
authors.lastname: Mills
authors.forename: Chris
authors.initials: C
authors.lastname: Davies
authors.forename: Scott
authors.initials: S
authors.lastname: Lamont
authors.forename: David
authors.initials: D
authors.lastname: Milne
authors.forename: Calum
authors.initials: C
authors.lastname: Cook
authors.forename: Peter
authors.initials: P
authors.lastname: Moore
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Sawyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005559:Formamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D005559:Formamides; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein