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

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

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

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

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

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.

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

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

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

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

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

3D structure of PDE5 complex with sildenafil

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

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

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

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

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 2013. 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