title: Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2.
abstract: Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.
authors.affiliation: Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. chris.desavi2@astrazeneca.com
authors.forename: Chris
authors.initials: C
authors.lastname: De Savi
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morley
authors.forename: Ian
authors.initials: I
authors.lastname: Nash
authors.forename: Galith
authors.initials: G
authors.lastname: Karoutchi
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13; D015032:Zinc