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 (K_i 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 (K_i values of 527, 154 and 59 nM, respectively).

2. Ro 32-3555 inhibited interleukin-1α (IL-1α)-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.