Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2

Chris De Savi; Andrew D Morley; Ian Nash; Galith Karoutchi; Ken Page; Attilla Ting; Stefan Gerhardt

doi:10.1016/j.bmcl.2011.11.034

Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2

Bioorg Med Chem Lett. 2012 Jan 1;22(1):271-7. doi: 10.1016/j.bmcl.2011.11.034. Epub 2011 Nov 16.

Authors

Chris De Savi¹, Andrew D Morley, Ian Nash, Galith Karoutchi, Ken Page, Attilla Ting, Stefan Gerhardt

Affiliation

¹ Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. [email protected]

PMID: 22153941
DOI: 10.1016/j.bmcl.2011.11.034

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.

MeSH terms

Animals
Chemistry, Pharmaceutical / methods*
Dogs
Drug Design
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Matrix Metalloproteinase 13 / chemistry*
Matrix Metalloproteinase Inhibitors*
Models, Chemical
Models, Molecular
Osteoarthritis / drug therapy
Rats
Solubility
Structure-Activity Relationship
Zinc / chemistry*

Substances

Enzyme Inhibitors
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 13
Zinc