Pharmacological separation between peripheral and central functions of cyclooxygenase-2 with CIAA, a novel cyclooxygenase-2 inhibitor.
There are many reports concerning the physiological and pathological involvement of cyclooxygenase (COX)-2 in the central nervous system and peripheral tissue cells. Selective COX-2 inhibitors that mainly distribute peripherally have not been reported thus far. Therefore central and peripheral roles of COX-2 remain classified pharmacologically. In this study, in vivo pharmacological profiles of CIAA ([6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid), a novel selective COX-2 inhibitor which distributes at higher concentrations in plasma than in brain, were compared with those of well-known selective COX-2 inhibitors, celecoxib and rofecoxib. Additionally, the possibility of pharmacological separation between peripheral and central actions of COX-2 with the inhibitors was investigated. CIAA selectively inhibited COX-2 activity compared with COX-1 in in vitro assays with rat whole blood. The compound exhibited lower brain penetration and higher plasma concentration (the brain/plasma concentration ratio was approximately 0.02) than celecoxib and rofecoxib after oral administration. Therefore, CIAA is mainly expected to act peripherally. Edema and prostaglandin E2 (PGE2) production in Carrageenan-injected rat paws, and pyrexia and PGE2 production in the brain in lipopolysaccharide (LPS)-injected rats were measured in in vivo experiments. CIAA exhibited lower ratios of anti-pyretic/anti-edematous activities and of inhibitory activities of PGE2 production in brain/paw than those of celecoxib and rofecoxib, and these ratios well-reflected brain/plasma concentration ratios. In conclusion, we discovered a novel selective COX-2 inhibitor, CIAA, which distributes at higher concentrations in plasma than in brain, which would make possible the pharmacological separation of the peripheral and central functions of COX-2.
Okumura
Takako
T
Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. Takako_Okumura@Pfizer.com
Murata
Yoko
Y
Hizue
Masanori
M
Matsuura
Tomomi
T
Naganeo
Rie
R
Kanai
Yoshihito
Y
Murase
Akio
A
Sakakibara
Ayano
A
Fujita
Isami
I
Nakao
Kazunari
K
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002351:Carrageenan; D000068579:Celecoxib; D002723:Chlorobenzoates / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced / Q000378:metabolism; D006614:Hindlimb; D007210:Indoleacetic Acids / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D007783:Lactones / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D013450:Sulfones / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D014018:Tissue Distribution
C479620:(6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl)acetic acid; D002723:Chlorobenzoates; D052246:Cyclooxygenase 2 Inhibitors; D007210:Indoleacetic Acids; D007783:Lactones; D008070:Lipopolysaccharides; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone