Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits.
Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.
MacPherson
L J
LJ
Research Department, Novartis Pharmaceuticals, Summit, New Jersey 07901, USA.
Bayburt
E K
EK
Capparelli
M P
MP
Carroll
B J
BJ
Goldstein
R
R
Justice
M R
MR
Zhu
L
L
Hu
S
S
Melton
R A
RA
Fryer
L
L
Goldberg
R L
RL
Doughty
J R
JR
Spirito
S
S
Blancuzzi
V
V
Wilson
D
D
O'Byrne
E M
EM
Ganu
V
V
Parker
D T
DT
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006877:Hydroxamic Acids; D066298:In Vitro Techniques; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism; D013449:Sulfonamides
C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D013449:Sulfonamides; D013373:Substance P