Phosphinic acid-based MMP-13 inhibitors that spare MMP-1 and MMP-3.
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.
Reiter
Lawrence A
LA
Pfizer Inc, Global Reseach & Development, Groton Laboratories, Eastern Point Rd., 06340, Groton, CT, USA. lawrence_a_reiter@groton.pfizer.com
Mitchell
Peter G
PG
Martinelli
Gary J
GJ
Lopresti-Morrow
Lori L
LL
Yocum
Sue A
SA
Eskra
James D
JD
D017364:Collagenases / Q000737:chemistry; D007202:Indicators and Reagents; D007536:Isomerism; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry / Q000187:drug effects*; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1