title: Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis.
abstract: A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.
authors.affiliation: Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, 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: Yvonne
authors.initials: Y
authors.lastname: Sawyer
authors.forename: David
authors.initials: D
authors.lastname: Milne
authors.forename: Chris
authors.initials: C
authors.lastname: Davies
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.forename: Scott
authors.initials: S
authors.lastname: Lamont
authors.forename: Peter D
authors.initials: PD
authors.lastname: Smith
authors.forename: Jonathon
authors.initials: J
authors.lastname: Tart
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.forename: Peter
authors.initials: P
authors.lastname: Moore
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D005559:Formamides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D005559:Formamides; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein