Viagra (Sildenafil) 2007311872 라진환 2007314223 안동준 Medicinal Chemistry o 2007311872 라진환 2007314223 안동준

Derivation of a Word : Viagra Vigor Viagra Niagara o

Development History o

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

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

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

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.

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

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).

Summary: History of Sildenafil

Mechanism of action

PDE Family

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

The NO/cGMP Signalling Pathway

Working Model of PDE5

Structure Activity Relationship(SAR) of Sildenafil

Comparison of Structure in cGMP and Sildenafil

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)

Stereo View of the Active Site of PDE5 Magnesium Zinc Sildenafil

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

PDE5-GMP Complex

Sildenafil-binding Pocket of PDE5

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

IC50 of Sildenafil Analogues R1 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

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

IC50 of Sildenafil Analogues R1 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

PDE5 Selectivity & Adverse Effect

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

Adverse Effect on Eyes

Vasodilation Flushing Tachycardia IC50 values (μM) Drug PDE5 PDE6(rod) PDE6(cone) PDE6(cone)/PDE5 Sildenafil 0.00350 0.037 0.034 9.7 Tadalafil 0.00674 1.26 1.30 193 PDE1 0.218 >30 Vasodilation Flushing Tachycardia Sildenafil Tadalafil

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