RO-32-3555, AN ORALLY-ACTIVE COLLAGENASE INHIBITOR, PREVENTS CARTILAGE BREAKDOWN IN-VITRO AND IN-VIVO

1 Ro 32-3555 lidinyl)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 sel ective inhibitor of collagenases over the related human matrix metallo proteinases stromelysin 1, and gelatinases A and B (K-i values of 527, 154 and 59 nM, respectively). 2 Ro 32-3555 inhibited interleukin-1 al pha (IL-1 alpha)-induced cartilage collagen degradation in vitro in bo vine nasal cartilage explants (IC50 = 60 nM). 3 Ro 32-3555 was well ab sorbed in rats when administered orally. Systemic exposure was dose re lated, 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 c artilage 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 Pr opionibacterium acnes. 6 Ro 32-3555 is a potential therapy for the tre atment of the chronic destruction of articulating cartilage in both rh eumatoid and osteoarthritis.