title: 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.
authors: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Junko
authors: J
authors: Imanishi
authors: Yoshiaki
authors: Y
authors: Morita
authors: Eiji
authors: E
authors: Yoshimi
authors: Kanae
authors: K
authors: Kuroda
authors: Tomoko
authors: T
authors: Masunaga
authors: Kaoru
authors: K
authors: Yamagami
authors: Masako
authors: M
authors: Kuno
authors: Emi
authors: E
authors: Hamachi
authors: Satoshi
authors: S
authors: Aoki
authors: Fumie
authors: F
authors: Takahashi
authors: Katsuya
authors: K
authors: Nakamura
authors: Susumu
authors: S
authors: Miyata
authors: Yoshitaka
authors: Y
authors: Ohkubo
authors: Seitaro
authors: S
authors: Mutoh
mesh_terms: D019342:Acetic Acid; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D016466:CHO Cells; D002351:Carrageenan; D006224:Cricetinae; D003412:Cricetulus; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D013276:Stomach Ulcer / Q000139:chemically induced; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561773:3-methoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011994:Recombinant Proteins; D014230:Triazoles; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019342:Acetic Acid