Abstract |
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.
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Authors | E J Lewis, J Bishop, K M Bottomley, D Bradshaw, M Brewster, M J Broadhurst, P A Brown, J M Budd, L Elliott, A K Greenham, W H Johnson, J S Nixon, F Rose, B Sutton, K Wilson |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 121
Issue 3
Pg. 540-6
(Jun 1997)
ISSN: 0007-1188 [Print] England |
PMID | 9179398
(Publication Type: Journal Article)
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Chemical References |
- Imidazoles
- Matrix Metalloproteinase Inhibitors
- Protease Inhibitors
- Ro 32-3555
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Topics |
- Administration, Oral
- Animals
- Arthritis, Experimental
(drug therapy)
- Cartilage
(drug effects, metabolism)
- Cattle
- Humans
- Imidazoles
(pharmacokinetics, pharmacology)
- Male
- Matrix Metalloproteinase Inhibitors
- Protease Inhibitors
(pharmacokinetics, pharmacology)
- Rats
- Rats, Sprague-Dawley
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