Viagra (Sildenafil) 2007311872 2007314223 Medicinal Chemistry
o 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 679725) C-terminal helical bundle domain (residues 726860) Sildenafil Tadalafil N-terminal cyclin-fold domain (residues 537678) 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 (M) 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 Thank you