Antinociceptive effects of AS1892802, a novel Rho kinase inhibitor, in rat models of inflammatory and noninflammatory arthritis.
Rho kinase (ROCK) is involved in various physiological functions, including cell motility, vasoconstriction, and neurite extension. Although a functional role of ROCK in nociception in the central nervous tissue has been reported in neuropathy, the peripheral function of this protein in hyperalgesia is not known. In this study, antinociceptive effects of AS1892802 [1-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-(pyridin-4-yl)phenyl]urea], a novel and highly selective ROCK inhibitor, were investigated in two rat models of arthritis. Orally administered AS1892802 exhibited potent antinociceptive effect in both an adjuvant-induced arthritis (AIA) model (inflammatory arthritis model) and a monoiodoacetate-induced arthritis (MIA) model (noninflammatory arthritis model), with an ED(50) of 0.15 mg/kg (MIA model). Fasudil, a ROCK inhibitor, and tramadol were also effective in both models; however, diclofenac was effective only in the AIA model. The onset of antinociceptive effect of AS1892802 was as fast as those of tramadol and diclofenac. AS1892802 did not induce gastric irritation or abnormal behavior. Because AS1892802 rarely penetrates the central nervous tissue and is also effective by intra-articular administration, it seemed to function peripherally. These results suggest that AS1892802 has an attractive analgesic profile for the treatment of severe osteoarthritis pain.
Yoshimi
Eiji
E
Pharmacology Research Laboratories, Astellas Pharma Inc., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan. eiji.yoshimi@jp.astellas.com
Kumakura
Fumiyo
F
Hatori
Chie
C
Hamachi
Emi
E
Iwashita
Akinori
A
Ishii
Noe
N
Terasawa
Takeshi
T
Shimizu
Yasuaki
Y
Takeshita
Nobuaki
N
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000700:Analgesics; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005620:Freund's Adjuvant; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007461:Iodoacetates; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D014147:Tramadol / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C552258:1-(2-hydroxy-1-phenylethyl)-3-(4-(pyridin-4-yl)phenyl)urea; D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007461:Iodoacetates; D010671:Phenylurea Compounds; D011725:Pyridines; D004008:Diclofenac; D014147:Tramadol; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D005620:Freund's Adjuvant; D054460:rho-Associated Kinases; D015232:Dinoprostone; C049347:fasudil