SILDENAFIL

DRUG DISCOVERYPIRATLA MALLIKA10036366

Sildenafil citrate, commonly called as “Viagra” was first discovered by Pfizer company in U.K.

It was initially used to study its effects for the treatment of angina pectoris and hypertension.

It was found to be effective for penile errections than on cardiovascular diseases.

First clinical trials were conducted in Morriston Hospital in Swansea under the guidance of Prof. Lan Osterloh.

The drug was patented in 1996 and approved by U.S FDA on March 27th 1998.

IUPAC name of Sildenafil citrate is 1-[4-ethoxy-3(6,7- dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolol[4,3- d]pyrimidine-5-yl)phenyl sulfonyl]-4-methyl piperazine.

Target is cyclic guanosine monophosphate phosphodiesterase type 5 receptor.

Fluforma is a company which found the genome explorations and target identification through affymetrix microarrays.

High throughput functional assays of Si Rna’s inhibit the expression of target, chromatographic techniques, spectrophotometric methods, adsorptive stripping voltametry.

Gingel et.al showed that a 50mg dose given daily for 28 days consecutively improved errections in almost 90% of patients.

Structural validation techniques are NMR technique, Infrared spectrum, HPLC, Mass spectroscopy and Liquid chromatography.

Ref: copyright @2006,naturepublishing group nature reviews/drug discovery

When clinical trials aimed to develop a potent PDE5 inhibitor which increases the level of c-GMP using Zapirnast, it did not show effect on cardiovascular system.

By altering the structure and by increasing the lipophilicity of the drug by optimisation of structural activity relationship, it showed marked effects on erectile function in corpus cavernosum in penis.

This showed the evolution of sildenafil citrate.

The other analogues of sildenafil are Vardenafil(Levitra), Tadalfil(Cialis), Revatio

Jie-Jack Li et.al(2004), contemporary drug synthesis

The first clinical trials on Zapirnast found that, it was weak selective PDE5 inhibitor for the treatment of angina pectoris.

By structural alteration of the drug with alkyl positions resulted in the formation of N-methyl piperazine sulfonamide resulted in the increased potency.

By increasing the lipophilicity of the drug resulted in formation of Sildenafil citrate.

Jie-Jack Li et.al(2004), contemporary drug synthesis

2-ethoxy benzoic acid hydrochloride triethylamine amide form of hydrochloride triethylamine

sildenafil

SYNTHESIS

Jie-Jack Li et.al (2004), contemporary drug synthesis

1 2

31.Chloro sulphonic acid,sulphonyl chloride 0 degrees.2.Ethoxide acetate pd/c,H2 at 50 degrees.3.Kot-Bu,t-BuOH,reflux,HCl, 95% yield.

QSAR

ZAPIRNAST

Alteration of “R1” from methyl to propyl provides enhancement in the potency of the drug. Substitution of sulfonamide group in “R2” increases lipophilicity and increases the solubility of the compound.

N-Methyl piperazine sulfonamide ring is responsible for the potency of the drug.

Jie-Jack Li et.al(2004), contemporary synthesis

Sildenafil is rapidly absorbed with absolute bioavailability of 40%, it is cleared by hepatic microsomal isoenzymes CYP3A4 and CYP2C9 and excreted.

POSOLOGY

& EFFICACY

Sildenafil is available in 25mg, 50mg, 100mg.

Efficacy of erectile function can be scored by five domains, namely erectile function, orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction by international index.

It should not be administered with organic nitrates and calcium channel antagonist, alpha blocker drugs.

SIDE EFFECTS

Priapism may occur if erections lasts longer than 4hrs.

Heart attack, irregular heart beats, headache, flushing, etc.

On rare occasions death may occur due to improper use or when contraindicated by other drugs when concomitantly used by hypertensive patients.

Jie-Jack Lie et.al (2004) contemporary drug synthesis.

Long-Chu Lau, P.Ganesan Aadikan 541(2006)184-190 european journal of pharmacology.

Marvin M.Goldenberg ,ph.d/vol 20,no.6(1998) safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction , Clinical Therapeutics.

Sildenafil Medicine Patient U.K.htm.

J.E.Antunes et.al / Bio org.Med.Chem.16(2008)7599-7606.

http:// Sildenafil Medicine plus drug infpormation.htm.

Robert B.Moreland et.al research and clinical implications in erectile dysfunction.

Graham Jackson et.al the american journal of cardiology vol83(5A)March4,1999

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