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).
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.
Li
Wei
W
Chemical Sciences, Inflammation, and Drug Safety and Metabolism, Wyeth Research, Cambridge, Massachusetts 02140, USA.
Li
Jianchang
J
Wu
Yuchuan
Y
Wu
Junjun
J
Hotchandani
Rajeev
R
Cunningham
Kristina
K
McFadyen
Iain
I
Bard
Joel
J
Morgan
Paul
P
Schlerman
Franklin
F
Xu
Xin
X
Tam
Steve
S
Goldman
Samuel J
SJ
Williams
Cara
C
Sypek
Joseph
J
Mansour
Tarek S
TS
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
C540173:2-(8-(methoxycarbonylamino)dibenzo(b,d)furan-3-sulfonamido)-3-methylbutanoic acid; D001572:Benzofurans; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides