title: Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo.
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.
authors.affiliation: Roche Discovery Welwyn, Welwyn Garden City, Herts.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lewis
authors.forename: J
authors.initials: J
authors.lastname: Bishop
authors.forename: K M
authors.initials: KM
authors.lastname: Bottomley
authors.forename: D
authors.initials: D
authors.lastname: Bradshaw
authors.forename: M
authors.initials: M
authors.lastname: Brewster
authors.forename: M J
authors.initials: MJ
authors.lastname: Broadhurst
authors.forename: P A
authors.initials: PA
authors.lastname: Brown
authors.forename: J M
authors.initials: JM
authors.lastname: Budd
authors.forename: L
authors.initials: L
authors.lastname: Elliott
authors.forename: A K
authors.initials: AK
authors.lastname: Greenham
authors.forename: W H
authors.initials: WH
authors.lastname: Johnson
authors.forename: J S
authors.initials: JS
authors.lastname: Nixon
authors.forename: F
authors.initials: F
authors.lastname: Rose
authors.forename: B
authors.initials: B
authors.lastname: Sutton
authors.forename: K
authors.initials: K
authors.lastname: Wilson
mesh_terms: 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
chemical_list: D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C106997:Ro 32-3555