Drug Design of COX-1 & COX-2 Inhibitors

1. DESIGN OF SELECTIVE
COX-2 INHIBITORS
(ADVANCED MEDICINAL CHEMISTRY)
PRESENTED BY:-
SIDDHARTH JAIN
M.Pharma (1ST SEM)
School of pharmacy, DAVV,Indore

2. INTRODUCTION TO SELECTIVE COX-2
INHIBITORS
 PGs is formed by 2 enzyme namely COX-1&COX-2 that
have different action in the body.
 Selective cox-2 inhibitors are type of NSAIDS that
particularly binds to cox-2 enzyme ,which is responsible
for inflammation and pain.
 The therapeutic anti-inflammatory activity is shown by
the inhibition of cox-2 enzyme which is selective inhibitor.
 COX-2 not play important role in the protection of
stomach & intestine.
 COX-2 is not normally found in the cells,its existence is
induced but its expression can be increased dramatically
by the action macrophages & by the immune system.

3. REASON FOR SELECTIVE COX-2
INHIBITORS
 NSAIDS that block non-selectively COX enzyme & blocks
production of PGs.
 Therefore ,inflammation ,pain & fever are reduced by all
COX inhibitors since the PGs that protect the stomach
ulceration & also promotes blood clotting are also reduced
after inihibition of COX-1.
 NSAIDS increases the risk ulcer in stomach and bleeding.
 THERE ARE SOME REASONS FOR SELECTIVE COX-2
INHIBITORS :-
 Ulcer produced by degradation of mucosal membrane
 Bleeding from stomach after ulceration

4. Non selective cox inhibitors blocks both cox enzyme that
result in deprotection of gastric mucosa leads to ulceration in
the stomach and also blocks activation of platelets finally
leads to bleeding.

5.  REASON FOR SELECTIVE COX-2
INHIBITORS
 Unlike older NSAIDS that blocks both COX-1 & COX-2
enzyme ; the newer are selective COX-2 inhibitors that
are only blocks to COX-2 enzyme (not COX-1 which
promotes stomach linning & blood clotting )
 They do not cause ulcers or increase the risk of bleeding
as much as the older NSAIDS cause.
ULCERATION
 NSAIDS directly degrades the mucus membrane of
stomach or by through PGs mediated effect which finally
release HCL from the inner mucus membrane guarding
the stomach from acid attack.

6.  PGs mediated effects are decreased mucin secretion
decrease bicarbonate secretion from acid pump and after
mucosal proliferation.
 BLEEDING FROM STOMACH ULCER
 Block the COX-1 enzyme inhibits the synthesis of
thromboxane A2 which activates platelets aggregation and
also blocks the blood clotting factor that cause bleed from
the ulcer or any site of the body where the COX-1 enzyme
is present.

7.  When COX-1 is blocked ,inflammation reduced and the
protection of the gastric mucosa is lost that causes ulcer in
stomach and also inhibit the aggregation of platelet formation
that finally results in bleeding.

9. COMPARATIVE STUDIES OF COX-1
&C0X-2 ENZYME
 COX-1 is expressed constitutively & COX-2 is inducible also
upregulated in response to growth factors but its mRNA &
protein found transiently ;thus, COX-2 is not generally found
in the differentiated cell it is only found when induction of the
inflammation occur at the site.
 COX-1 is readily found in the GI tract where it is believed to
protect against gastric damage.
 COX-2 found in only in leukocytes ,synoviocyte & in CNS to
paly a role in inflammation and fever.
 COX-2 do not inhibit platelet function as result major benefit
from bleeding and reduction in gastric ulcer formation.

10.  The change of a valine at position 523 in C0X-2 with a
relatively bulky isoleucine residue in COX-1 at the same
place of the active site of the enzyme resulted in a
structural change of the enzyme as well as better entry
to an additional side pocket in COX-2 enzyme, which is
necessary for COX-2 drug selectivity.
 In addition, the change of residue 434 from isoleucine to
valine in COX-2 allow the neighbouring Phe518 to swing
out from path for the expanding entry to the side space.


11.  In place of Histidine 513 in COX-1, COX-2 have Arginine 513
number of AA’s which affects the chemical surrounding of
the binding site where the arginine residue can have a
better binding interaction with polar moieties of substrate
entering the pocket.
 These makes the COX active site long hydrophobic channel
where the attachment of COX-2 inhibitors is more
convinient and easy.

13. RISE FOR THE DRUG DESIGN AND
DEVELOPMENT OF THE SELECTIVE COX-2
INHIBITORS
 The need for the design and development of the
selective COX-2 inhibitors was ulceration in gastric
mucosa and dysfunction of platelet aggregation.
 From the above information about the structure of COX-
2 enzyme and site for attachment of the selective COX-2
inhibitors the drugs are designed.
 In 1991 the existence of the COX-2 enzyme was
confirmed by being cloned by Dr. Dan Simmons at
Brigham Young university.
 Before confirmation of COX-2 existence the DUPONT
COMPANY developed compound Dup-697,that has
potent anti-inflammatory activity and not have
ulcergonic effect of NSAIDS.

14.  Once the COX-2 enzyme was identified Dup-697 is the
building block for synthesis of COX-2 inhibitors.
 This is used as lead compound for more analouges of
selective COX-2 inhibitors.
DUP-697

15. DRUG DESIGN OF SOME SELECTIVE
COX-2 INHIBITORS
 Generation of lead compounds is one of the
most significant phases in a drug discovery
approach. In a modern drug discovery
research, structure-activity relationships
(SAR) are widely applied in detecting new
leads for the optimization of receptor or
enzyme affinity, as well as the study of
pharmacokinetic and physicochemical
properties.
 Protein-ligand interactions play important
roles in structure-based drug design (SBDD)

16.  For instance, the COX-2 binding site has two extra pockets that
are absent in the COX-1 binding site. This information is
extremely significant and useful for designing COX-2 selective
inhibitors. The difference in the COX-2 binding pocket arises due
to a conformational alteration at Tyr355, that is attributed to
the existence of Ile523 in COX-1 as compared to Val523 in COX-2
which has a smaller side chain.
In addition, it has been reported that the replacement of
His513 in COX-1 by Arg513 in COX-2 plays a key role with
relation to the H-bond network in the COX-2 binding site. Entry
of ligands to the pockets of COX-2 is regulated by His90, Gln192
and Tyr355. The interaction of Arg513 with the bound drug is a
requirement for time dependent inhibition of COX-2.
LIGAND BINDING INTERACTION

18. SAR OF SELECTIVE COX-2 INHIBITORS

19. SOME IMPORTANT SELECTIVE COX-2
INHIBITORS THAT ARE DESIGNED

20. SOME DRUGS AND THEIR BINDINGS
CELECOXIB

21. PARECOXIB