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

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Abstract
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). Ro 32‐3555 inhibited interleukin‐1α (IL‐1α)‐induced cartilage collagen degradation in vitro in bovine nasal cartilage explants (IC50=60 nM). 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. 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.). 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. Ro 32‐3555 is a potential therapy for the treatment of the chronic destruction of articulating cartilage in both rheumatoid and osteoarthritis.