1. Speaker : Chin–Hsiang Tu 2008.12.23
Sildenafil
Speaker : Chin–Hsiang Tu

2. Sildenafil (Viagra)
膜衣錠50 mg
膜衣錠100 mg

3. 化學式 : 1-〔4-ethoxy-3-(6,7-dihydro-1-methl-7-oxo-3-propyl-1H-pyrazolo〔4,3-d〕pyrimidin-5-yl) phenylsulphonyl〕-4-methylpiperazine citrate
實驗式 : C22H30N6O4S.C6H8O
分子量 : 666.7
Sildenafil
Viagra 威而鋼

4. Pharmacology
Viagra是一種口服有效，且對 cGMP-specific PDE5(phosphodiesterase type 5) 具有選擇性的抑制劑。
PDE5主要存在於平滑肌組織中。
Viagra 藉由抑制 PDE5避免 cGMP 被分解成 GMP, 來達到治療 Penis erectile dysfunction.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | AUGUST 2006 | 689

6. Designing history
Origins of the cGMP/PDE3 project at Pfizer in the mid-1980s. Ex. Minipress, Cardura ……
Nitrate act as mixed dilators of arteries and veins.
The therapeutic potential of nitrates is limited by the rapid induction of tachyphylaxis. (是一種矛盾現象,會產生跟原來目的完全相反的效果)
In 1986 Pfizer with the aim of developing a selective inhibitor of PDE5 and evaluating its preclinical pharmacology.
tachyphylaxis一字,源字希臘文 ,意指"快速"的tachy和"抵禦或障礙"的phylaxis而來
 tachyphylaxis是一種矛盾現象,一種藥會產生跟原來目的完全相反的效果

7. In 1989 UK-92,480 was selected to undergo further development and entered clinical trials in 1991.
In 1992, volunteers also reported penile erections as a side effect.
In mid-1993, UK-92,480 was looking less promising as a new treatment .
In 1998 , approval of sildenafil as Viagra by FDA as first oral treatment for erectile dysfunction.

8. Designing model Zaprinast Developed as an anti-allergy compound
Non-selective
PDE1
PDE3
PDE5
9.4 μM
58 μM
2.0 μM
Similar size, shape and dipoles
Intramolecular hydrogen bond forms planar strucuture

9. (1.) Pyrazolopyrimidinones
PDE1
PDE3
PDE5
9.4 μM
58 μM
2.0 μM
PDE1
PDE3
PDE5
3.3 μM
>100 μM
0.3 μM

10. (2.) Pyrazole substitution
PDE1
PDE3
PDE5
3.3 μM
>100 μM
0.3 μM
PDE1
PDE3
PDE5
790nM
>100 μM
27nM

11. (3.) Phenyl substitution
Need to reduce lipophilicity, increase solubility
Groups chosen to reduce log D , and maximum solubility.

12. (4.) Preferred compound PDE1 PDE3 PDE5 790nM >100 μM 27nM PDE1 PDE3

13. 3D structure of PDE5 complex with sildenafil

14. Preclinical Pharmacology - Vessels
Effect of sildenafil verse nitrate on nerve stimulated contraction of blood vessels in vivo.

15. Preclinical Pharmacology - Corp. Cav.
Effect of sildenafil on electrical field stimulated relaxation
of human corpus cavernosum
Sildenafil dose-dependently enhances relaxation of corpus cavernosum

16. Preclinical Pharmacology - Platelet
Effect of sildenafil on anti-aggregation action of SNP
Sildenafil has no direct effect on agonist-induced aggregation

17. Sildenafil
Viagra 威而鋼
Tadalafil
Cialis 犀利士
Vardenafil
Levitra 樂威壯

19. Market for drugs to treat ED
Expecting sales of ED therapies in the major markets to nearly double during the next several years, reaching US $3.5 billion in In that year, combined sales of tadalafil and vardenafil will account for more than 50% market share.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 3 | APRIL 2004 | 295