214
model inhibition was shown by selective inhibitors like SC58125 (IC 50 – ˃1000 μM
for COX 1 and 0.1 μM for COX 2) and SC558 (a celecoxib prototype; IC 50 –17.7 μM
for COX 1 and 0.0093 μM for COX 2) which exhibited good efficacy in rodent
models of inflammation, fever and pain (Figs. 9.13 and 9.14) (DeWitt 1999).
9.2.2.4 Structural Diversity of Cyclooxygenase Inhibitors
NSAIDs inhibit cyclooxygenase in production of prostaglandins in the treatment of
inflammatory musculoskeletal conditions. Most of the NSAIDs inhibit COX 1 and
COX 2. NSAIDs are known to be aspirin-like drugs because they follow a structural
diversity with a carboxylic acid functional group which follows the antiinflammatory, analgesic and antipyretic action. Further they exhibit the characteristic side effects, including suppression of blood clotting via inhibitory action on
platelet function (Flower 2003) and gastric intolerance.
Indomethacin analogue’s selectivity is not at the side of the cyclooxygenase
active site while substitutions take place at the top. 4-Bromobenzyl indomethacin
complex with COX 2 indicates that 4-bromobenzyl group makes van der Waals
contact with Leu503 at the terminal of the COX 2 active site. Phe503 in COX1 cannot easily replace as leucine by bromobenzyl group and the COX 1 active site thus
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
O
O
CH
O
O
O
N
N
O
HO
H
N
H
F
F F
F
F
O
F
F
C
C
Cl
Cl
N
H
N
N
N
CH 3
CH 3
CH 3
CH 3
CH 3 O
CHCO 2 H
CHOO 2 H
CH 2 CO 2 H
CHOO 2 H
CONH
CH 3
CH 3
CH 3
CH 3
O
NH
Cl
OH
Cl
Cl
O
S N
N
Aspirin
(Acetylsalicylic acid)
Salicylic acid
Phenylbutazone
Flufenamic acid
Mefenamic acid
Oxyphenbutazone
Naproxen
Piroxicam
Diclofenac
Indomethacin
Ibuprofen
Flurbiprofen
Ketoprofen
Meclofenamic acid
C CH 3
CH 3
CH 3
CH 3
O
O
C
N
H 3 C
H 3 C
Fig. 9.13 Structure of classical NSAIDs and related compounds
C.S. Sharanya and M. Haridas
model inhibition was shown by selective inhibitors like SC58125 (IC 50 – ˃1000 μM
for COX 1 and 0.1 μM for COX 2) and SC558 (a celecoxib prototype; IC 50 –17.7 μM
for COX 1 and 0.0093 μM for COX 2) which exhibited good efficacy in rodent
models of inflammation, fever and pain (Figs. 9.13 and 9.14) (DeWitt 1999).
9.2.2.4 Structural Diversity of Cyclooxygenase Inhibitors
NSAIDs inhibit cyclooxygenase in production of prostaglandins in the treatment of
inflammatory musculoskeletal conditions. Most of the NSAIDs inhibit COX 1 and
COX 2. NSAIDs are known to be aspirin-like drugs because they follow a structural
diversity with a carboxylic acid functional group which follows the antiinflammatory, analgesic and antipyretic action. Further they exhibit the characteristic side effects, including suppression of blood clotting via inhibitory action on
platelet function (Flower 2003) and gastric intolerance.
Indomethacin analogue’s selectivity is not at the side of the cyclooxygenase
active site while substitutions take place at the top. 4-Bromobenzyl indomethacin
complex with COX 2 indicates that 4-bromobenzyl group makes van der Waals
contact with Leu503 at the terminal of the COX 2 active site. Phe503 in COX1 cannot easily replace as leucine by bromobenzyl group and the COX 1 active site thus
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
CO 2 H
O
O
CH
O
O
O
N
N
O
HO
H
N
H
F
F F
F
F
O
F
F
C
C
Cl
Cl
N
H
N
N
N
CH 3
CH 3
CH 3
CH 3
CH 3 O
CHCO 2 H
CHOO 2 H
CH 2 CO 2 H
CHOO 2 H
CONH
CH 3
CH 3
CH 3
CH 3
O
NH
Cl
OH
Cl
Cl
O
S N
N
Aspirin
(Acetylsalicylic acid)
Salicylic acid
Phenylbutazone
Flufenamic acid
Mefenamic acid
Oxyphenbutazone
Naproxen
Piroxicam
Diclofenac
Indomethacin
Ibuprofen
Flurbiprofen
Ketoprofen
Meclofenamic acid
C CH 3
CH 3
CH 3
CH 3
O
O
C
N
H 3 C
H 3 C
Fig. 9.13 Structure of classical NSAIDs and related compounds
C.S. Sharanya and M. Haridas