1. Academic Validation
  2. Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo

Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo

  • Br J Pharmacol. 1997 Jun;121(3):540-6. doi: 10.1038/sj.bjp.0701150.
E J Lewis 1 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
Affiliations

Affiliation

  • 1 Roche Discovery Welwyn, Welwyn Garden City, Herts.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19677
    99.81%, Collagenase Inhibitor
    MMP