Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1

Lawrence A Reiter; Ralph P Robinson; Kim F McClure; Christopher S Jones; Matthew R Reese; Peter G Mitchell; Ivan G Otterness; Marcia L Bliven; Jennifer Liras; Santo R Cortina; Kathleen M Donahue; James D Eskra; Richard J Griffiths; Mary E Lame; Arturo Lopez-Anaya; Gary J Martinelli; Shunda M McGahee; Sue A Yocum; Lori L Lopresti-Morrow; Lisa M Tobiassen; Marcie L Vaughn-Bowser

doi:10.1016/j.bmcl.2004.04.083

Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3389-95. doi: 10.1016/j.bmcl.2004.04.083.

Affiliation

¹ Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. [email protected]

PMID: 15177439
DOI: 10.1016/j.bmcl.2004.04.083

Abstract

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.

MeSH terms

Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Hydroxamic Acids / chemistry
Matrix Metalloproteinase 1 / metabolism*
Matrix Metalloproteinase 13
Matrix Metalloproteinase Inhibitors*
Matrix Metalloproteinases / metabolism
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Pyrans / chemistry
Structure-Activity Relationship
Sulfonamides / chemistry

Substances

Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Pyrans
Sulfonamides
MMP13 protein, human
Matrix Metalloproteinase 13
Matrix Metalloproteinases
Matrix Metalloproteinase 1