1. Viagra (Sildenafil) 2007311872 라진환 2007314223 안동준 Medicinal Chemistryo
라진환
안동준

2. Derivation of a Word : Viagra
Vigor
Viagra
Niagara o

3. Development History o

4. Origins of the cGMP/PDE5 Project
In the mid-1980s, cardiovascular research programme at the Pfizer.
Pfizer considered the therapeutic possibilities of modulating intracellular cGMP level
In 1986, Pfizer formed a project team with the aim of developing a selective inhibitor of PDE5 o
the team synthesized highly potent inhibitors of PDE5: Sildenafil

5. Clinical Development Programme for Angina
Good potency and selectivity for PDE 5
Moderate vasodilatory effect
Abrogated platelet aggregation
Inhibition of thrombus reformation in a damaged carotid artery

6. Looking Less Promising Drug for Angina Pectoris
The relatively short half-life for the chronic treatment of angina
Administration at least three times per day
pharmacodynamic interaction between Sildenafil and Nitrates
Contraindication in patients taking nitrates
Side effect
Headaches, flushing, indigestion and muscleaches

7. Thoughts Turn to Erectile Dysfunction
Reported penile erections in phase I study.
Decision to undertake pilot studies in ED
Clinical studies in ED
Some volunteers also reported penile erections as a side effect. Initially this was not considered to be of major significance, because the volunteers were reporting these effects after a mere several days of UK-92,480 administration.

8. Registration and Marketing of Viagra for ED.
The FDA approval for the treatment of ED in March 1998.

9. Thoughts Turn to Pulmonary Hypertension
Observed upregulation of PDE5 gene expression in pulmonary hypertensive lungs.
Pivotal trial and approval of sildenafil for the treatment of PAH (SUPER-1 study).

10. Summary: History of Sildenafil

11. Mechanism of action

12. PDE Family

13. Phosphodiesterase(PDE) 5
Present in the smooth muscle of the systemic vasculature, and in platelets
Exclusively catalyses the breakdown of cGMP

14. The NO/cGMP Signalling Pathway

15. Working Model of PDE5

16. Structure Activity Relationship(SAR) of Sildenafil

17. Comparison of Structure in cGMP and Sildenafil

18. PDE5 Tertiary Structure
Linker helical domain (residues 679–725)
C-terminal helical bundle domain (residues 726–860)
Sildenafil
Tadalafil
N-terminal cyclin-fold domain (residues 537–678)

19. Stereo View of the Active Site of PDE5
Magnesium
Zinc
Sildenafil

20. PDE5-Sildenafil Complex
Gln817
NH2 O
Gln775
CH3
Ala767 NH
Trp853
Hydrogen Bonding

21. PDE5-GMP Complex

22. Sildenafil-binding Pocket of PDE5

23. Contour plots of CoMFA model
Electropositive group favored
Bulky substitution favored
Electronegative group favored
Bulky substitution disfavored

24. IC50 of Sildenafil AnaloguesR1
pIC50
-OEt
7.57 -H
5.35
-OH
6.00
-OCH2CPr
6.02
-NO2
5.36
-NHSO2Me
6.11 R2
pIC50
-CH3
8.44
-CH2CH2OH
8.72
-CONH2
8.68 -H
8.24

25. Contour plots of CoMFA model
Electropositive group favored
Bulky substitution favored
Electronegative group favored
Bulky substitution disfavored

26. IC50 of Sildenafil AnaloguesR1
pIC50
-OEt
7.57 -H
5.35
-OH
6.00
-OCH2CPr
6.02
-NO2
5.36
-NHSO2Me
6.11 R2
pIC50
-CH3
8.44
-CH2CH2OH
8.72
-CONH2
8.68 -H
8.24
U-V-X-Y
pIC50
N-C-N-C
9.22
C-C-N-N
8.18
C-N-C-N
8.11

27. PDE5 Selectivity & Adverse Effect

28. Selectivity of Sildenafil
PDE6/PDE5(ID50) = 9.7
PDE6(Vision): Distribution in rod and cone photoreceptor cells.

29. Adverse Effect on Eyes

30. Vasodilation Flushing Tachycardia
IC50 values (μM)
Drug
PDE5
PDE6(rod)
PDE6(cone)
PDE6(cone)/PDE5
Sildenafil
0.037
0.034
9.7
Tadalafil
1.26
1.30
193
PDE1
0.218
>30
Vasodilation Flushing Tachycardia
Sildenafil
Tadalafil

31. Thank you