title: A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).
abstract: Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.
authors.affiliation: Chemical Sciences, Inflammation, and Drug Safety and Metabolism, Wyeth Research, Cambridge, Massachusetts 02140, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jianchang
authors.initials: J
authors.lastname: Li
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Rajeev
authors.initials: R
authors.lastname: Hotchandani
authors.forename: Kristina
authors.initials: K
authors.lastname: Cunningham
authors.forename: Iain
authors.initials: I
authors.lastname: McFadyen
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.forename: Franklin
authors.initials: F
authors.lastname: Schlerman
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: Joseph
authors.initials: J
authors.lastname: Sypek
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D011994:Recombinant Proteins; D012756:Sheep; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C540173:2-(8-(methoxycarbonylamino)dibenzo(b,d)furan-3-sulfonamido)-3-methylbutanoic acid; D001572:Benzofurans; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides