Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor.

ABSTRACT

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30 22 mg/kg; diclofenac ED30 3.6 mg/kg, rofecoxib ED30 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50 17 mg/kg; diclofenac ED50 1.4 mg/kg, rofecoxib ED50 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50 19 mg/kg; diclofenac ED50 14 mg/kg, rofecoxib ED50 >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50 1.8 mg/kg; diclofenac ED50 1.0mg/kg, rofecoxib ED50 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL >320 mg/kg; diclofenac NOEL <1mg/kg, rofecoxib NOEL 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.