217
first compound (Fig. 9.18a) was synthesized and has an IC 50 = 0.24 μM for COX 1
and IC 50 > 100 μM for COX 2 (Talley 1999). So many lead compounds were thus
developed including SC58125 (IC 50 – ˃1000 μM for COX 1 and 0.1 μM for COX 2)
(Zimmermann et al. 1998) (Fig. 9.18b). Another designed compound (Fig. 9.18c)
which contains an azide group has a potent inhibitory activity (COX 2 IC 50 = 1.55
μM, COX 1 IC 50 > 100 μM) (Habeeb et al. 2001). Celecoxib is an extensively studied drug molecule that has an IC 50 of 0.04 μM for COX 2 and 13 μM for COX 1
(Fig. 9.18d).
Diarylheterocycles with a Central 5-Membered Isoxazole Ring Isoxazole significantly inhibits cyclooxygeanse (COX 2 IC 50 = 0.18 μM, COX 1 IC 50 > 1000 μM)
(Talley 1999) and has a better in vivo activity also. Its derivatives also showed better
inhibition (Valdecoxib (a) COX 2 IC 50 = 0.005 μM, COX 1 IC 50 = 140 μM) (Habeeb
et al. 2001). Valdecoxib is a second-generation COX 2 selective drug with antiinflammatory and analgesic properties but withdrawn from market due to severe
side effects. Other two isoxazole regio isomers were synthesized and are selective
inhibitors of COX 2 [Compound (b): COX 2 IC 50 < 0.005 μM, COX 1 IC 50 > 500
μM; Compound (c) COX 2 IC 50 = 0.23 μM, COX 1; IC 50 = 256 μM] (Habeeb et al.
2001) (Fig. 9.19).
Diarylheterocycles Possess a Central 5-Membered Furanone Ring These compounds also possess COX-2 inhibitory activity with an IC 50 of 0.01 μM for COX 2
and 4.7 μM for COX 1 (a) (Habeeb et al. 2001). Para-SO 2 NH 2 (b) substituent of the
first compound resulted in decreased activity. Rofecoxib (c) comes under this
II
SC-57666
DuP-697
F
F
F
S
Br
SO 2 Me
SO 2 NH 2
SO 2 Me
Fig. 9.17 Chemical structure of COX inhibitors
F
F
N
N
N
N
N
N
Me
N N
F 3 C
Me
N 3
CN
SO 2 Me
SO 2 Me
SO 2 NH 2
CF 3
CF 3
a
b
c
d
Fig. 9.18 Chemical structure of COX inhibitors with a central 5-membered pyrazole ring
9 Anti-inflammatory Molecules: Enzyme Inhibitors
first compound (Fig. 9.18a) was synthesized and has an IC 50 = 0.24 μM for COX 1
and IC 50 > 100 μM for COX 2 (Talley 1999). So many lead compounds were thus
developed including SC58125 (IC 50 – ˃1000 μM for COX 1 and 0.1 μM for COX 2)
(Zimmermann et al. 1998) (Fig. 9.18b). Another designed compound (Fig. 9.18c)
which contains an azide group has a potent inhibitory activity (COX 2 IC 50 = 1.55
μM, COX 1 IC 50 > 100 μM) (Habeeb et al. 2001). Celecoxib is an extensively studied drug molecule that has an IC 50 of 0.04 μM for COX 2 and 13 μM for COX 1
(Fig. 9.18d).
Diarylheterocycles with a Central 5-Membered Isoxazole Ring Isoxazole significantly inhibits cyclooxygeanse (COX 2 IC 50 = 0.18 μM, COX 1 IC 50 > 1000 μM)
(Talley 1999) and has a better in vivo activity also. Its derivatives also showed better
inhibition (Valdecoxib (a) COX 2 IC 50 = 0.005 μM, COX 1 IC 50 = 140 μM) (Habeeb
et al. 2001). Valdecoxib is a second-generation COX 2 selective drug with antiinflammatory and analgesic properties but withdrawn from market due to severe
side effects. Other two isoxazole regio isomers were synthesized and are selective
inhibitors of COX 2 [Compound (b): COX 2 IC 50 < 0.005 μM, COX 1 IC 50 > 500
μM; Compound (c) COX 2 IC 50 = 0.23 μM, COX 1; IC 50 = 256 μM] (Habeeb et al.
2001) (Fig. 9.19).
Diarylheterocycles Possess a Central 5-Membered Furanone Ring These compounds also possess COX-2 inhibitory activity with an IC 50 of 0.01 μM for COX 2
and 4.7 μM for COX 1 (a) (Habeeb et al. 2001). Para-SO 2 NH 2 (b) substituent of the
first compound resulted in decreased activity. Rofecoxib (c) comes under this
II
SC-57666
DuP-697
F
F
F
S
Br
SO 2 Me
SO 2 NH 2
SO 2 Me
Fig. 9.17 Chemical structure of COX inhibitors
F
F
N
N
N
N
N
N
Me
N N
F 3 C
Me
N 3
CN
SO 2 Me
SO 2 Me
SO 2 NH 2
CF 3
CF 3
a
b
c
d
Fig. 9.18 Chemical structure of COX inhibitors with a central 5-membered pyrazole ring
9 Anti-inflammatory Molecules: Enzyme Inhibitors