Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo.
1. Ro 32-3555 (3(R)-(cyclopentylmethyl)-2(R)-[(3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl)methyl]-4-oxo-4-piperidinobutyrohydroxamic acid) is a potent, competitive inhibitor of human collagenases 1, 2 and 3 (Ki values of 3.0, 4.4 and 3.4 nM, respectively). The compound is a selective inhibitor of collagenases over the related human matrix metalloproteinases stromelysin 1, and gelatinases A and B (Ki values of 527, 154 and 59 nM, respectively). 2. Ro 32-3555 inhibited interleukin-1 alpha (IL-1 alpha)-induced cartilage collagen degradation in vitro in bovine nasal cartilage explants (IC50 = 60 nM). 3. Ro 32-3555 was well absorbed in rats when administered orally. Systemic exposure was dose related, with an oral bioavailability of 26% at a dose of 25 mg kg-1. 4. Ro 32-3555 prevented granuloma-induced degradation of bovine nasal cartilage cylinders implanted subcutaneously into rats (ED50 = 10 mg kg-1, twice daily, p.o.). 5. Ro 32-3555 dosed once daily for 14 days at 50 mg kg-1, p.o., inhibited degradation of articular cartilage in a rat monoarthritis model induced by an intra-articular injection of Propionibacterium acnes. 6. Ro 32-3555 is a potential therapy for the treatment of the chronic destruction of articulating cartilage in both rheumatoid and osteoarthritis.
Lewis
E J
EJ
Roche Discovery Welwyn, Welwyn Garden City, Herts.
Bishop
J
J
Bottomley
K M
KM
Bradshaw
D
D
Brewster
M
M
Broadhurst
M J
MJ
Brown
P A
PA
Budd
J M
JM
Elliott
L
L
Greenham
A K
AK
Johnson
W H
WH
Nixon
J S
JS
Rose
F
F
Sutton
B
B
Wilson
K
K
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C106997:Ro 32-3555