Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma.
MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.
Li
Wei
W
Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. weili@wyeth.com
Li
Jianchang
J
Wu
Yuchuan
Y
Rancati
Fabio
F
Vallese
Stefania
S
Raveglia
Luca
L
Wu
Junjun
J
Hotchandani
Rajeev
R
Fuller
Nathan
N
Cunningham
Kristina
K
Morgan
Paul
P
Fish
Susan
S
Krykbaev
Rustem
R
Xu
Xin
X
Tam
Steve
S
Goldman
Samuel J
SJ
Abraham
William
W
Williams
Cara
C
Sypek
Joseph
J
Mansour
Tarek S
TS
D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology; D055808:Drug Discovery; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors