Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1).
Structure activity relationships are described for a series of succinyl hydroxamic acids 4a-o as potent and selective inhibitors of matrix metalloprotease-3 (stromelysin-1). Optimisation of P1' and P3' groups gave compound 4j (MMP-3 IC50=5.9nM) which was >140-fold less potent against MMP-1 (IC50=51,000nM), MMP-2 (IC50=1790nM), MMP-9 (IC50=840nM) and MMP-14 (IC50=1900nM).
Fray
M J
MJ
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, UK. jonathan_fray@sandwich.pfizer.com
Dickinson
R P
RP
D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors