- Novel Cyclooxygenase-1-Selective Inhibitor -
Cyclooxygenase 1(COX-1) inhibition has been thought to be a major mechanism of gastric damage by
drugs (NSAIDs). Dr. Kakuta reported that TFAP [N-(5-amino-2-pyridinyl)-4-
(trifluoromethyl)benzamide)], which has a structure clearly different from those of currently available COX-1-
selective inhibitors, is a potent COX-1-selective inhibitor (COX-1: IC50 = 0.80 ± 0.05µM; COX-2: IC50 = 210 ±
TFAP causes little gastric damage in rats even at an oral dose of 300mg/kg, though it has an analgesic effect
at as low a dose as 10mg/kg. The results show that COX-1-selective inhibitors can be analgesic agents
without causing gastric damage.
Wako has launched TFAP as a novel COX-1-selective inhibitor.
Chemical Name : N-(5-amino-2-pyridinyl)
[ COX-1: IC50 = 0.80µM,
COX-2: IC50 = 210µM ]
Gastric Ulcer Formation Test using Rat Stomach
Photographs and gastric damage scores of TFAP, Indomethacin and Aspirin
b) treated with TFAP (300mg/kg; p.o. )
c) treated with indomethacin (10mg/kg; p.o. )
d) enlarged illustration of part c:
Scale bars indicate 5mm. White triangles indicate ulcers.
Gastric damage score was calculated by measur-
ing the lengths, in millimeters, and summing the
values for each rat. TFAP, indomethacin (IMN)
and aspirin were administered at 300, 10, and
30mg/kg, respectively. Data shown are the mean
± SEM (n = 4/group). The following indicates
significantly different from the vehicle: (**) p < 0.01
Analgesic Effect Tests
a) Acetic acid-induced writhing test in mice
Gray and black bars indicate number of writhes at 10 and
30mg/kg, respectively. Each value is the average of the
total number of writhes ± SEM
(n = 10-11/group).
test in rats
Open circles, circles, triangles, and squares indicate
vehicle, TFAP, indomethacin and aspirin, respectively.
Each compound was orally administered at 30 mg/kg.
Data shown are the average of the total number of pain-
related behaviors ± SEM (n = 8/group).
The followings indicate significant differences from the vehicle: (*) p < 0.05; (**) p < 0.01
Chorioallantoic Membrane (CAM) Assay
The angiogenesis activity of TFAP was evaluated by the
assay of chick chorioallantoic membrane (CAM). TFAP
inhibited CAM angiogenesis at a 300 ng/CAM.
TFAP was orally administered at 30 and 300 mg/kg.
Data shown are the average of blood vessels/egg ±
SEM (n = 6/group). The following indicates significant
difference from the vehicle: (*) p < 0.05
(Data was provided by Dr. Hiroki Kakuta, Division of Pharmaceutical Sciences, Okayama Univ. Graduate School of Medicine, Dentistry
and Pharmaceutical Sciences)
Kakuta, H., et al.: Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric
damage. Design and in vitro /in vivo evaluation of a Benzamide-type Cyclooxygenase-1- selective inhibitor, J. Med. Chem., 51,
Wako Catalog No. (Package Size)