Avanafil

Avanafil Basic information
Product Name:Avanafil
Synonyms:4-[[(3-Chloro-4-Methoxyphenyl)Methyl] aMino]-2-[(2S)-2-(hydroxyMethyl)-1-pyrrolidinyl]-N-(2-pyriMidinylMethyl)-5-pyriMidinecarboxaMide;4-((3-chloro-4-Methoxybenzyl)aMino)-2-(2-(hydroxyMethyl)pyrrolidin-1-yl)-N-(pyriMidin-2-ylMethyl)pyriMidine-5-carboxaMide;Avanafil PDE5 inhibitor;vanafil;(S)-4-((3-Chloro-4-Methoxybenzyl)aMino)-2-(2-(hydroxyMethyl)pyrrolidin-1-yl)-N-(pyriMidin-2-ylMethyl)pyriMidine-5-carboxaMide;Avanafil 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide;avanfil;(S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-(pyrimidin-2-yl
CAS:330784-47-9
MF:C23H26ClN7O3
MW:483.95
EINECS:000-000-0
Product Categories:Avanafil;Inhibitor;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;API;Chiral Reagents;Heterocycles;Inhibitors;330784-47-9
Mol File:330784-47-9.mol
Avanafil Structure
Avanafil Chemical Properties
Melting point 150-152°C
density 1.372
storage temp. Sealed in dry,Store in freezer, under -20°C
solubility DMSO (Slightly), Methanol (Slightly, Heated)
pka11.84±0.46(Predicted)
form Solid
color White to Off-White
InChIKeyWEAJZXNPAWBCOA-INIZCTEOSA-N
SMILESC1(N2CCC[C@H]2CO)=NC=C(C(NCC2=NC=CC=N2)=O)C(NCC2=CC=C(OC)C(Cl)=C2)=N1
CAS DataBase Reference330784-47-9(CAS DataBase Reference)
Safety Information
HS Code 29339900
MSDS Information
Avanafil Usage And Synthesis
DescriptionAvanafil (Zepeed) was approved by the Korean Health Ministry for the treatment of erectile dysfunction (ED) in August 2011. Avanafil is a highly selective type 5 phosphodiesterase (PDE5) inhibitor. Avanafil is reported to be the most selective PDE5 inhibitor on the market. The onset of Tmax and half-life also varies among the marketed PDE5 inhibitors. Sildenafil has a Tmax at 1 h and a half-life of 3–5 h. Vardenafil is somewhat similar with a Tmax of 0.6 h and a half-life of 4–6 h. Tadalafil has the longest half-life among the marketed drugs with a half-life of 17 h. Avanafil has a fast onset of action reaching Tmax in 0.6 h with a half-life of 1.2 h. A synthesis of avanafil (TA-1790) is described in the patent literature. The main elimination route of avanafil is through the bile and feces. Avanafil was also found to be reabsorbed through enterohepatic recirculation.
Chemical PropertiesWhite Solid
OriginatorMitsubishi Tanabe Pharma Corporation (Japan)
UsesAvanafil is a highly selective PDE5 inhibitor with IC50 of 1 nM.
UsesA phosphodiesterase (PDE5) inhibitor, used to treat erectile dysfunction.
DefinitionChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid with the amino group of pyrimidin-2-ylmethylamine Used for treatment of erectile dysfunction.
Brand nameZepeed
Clinical UseAvanafil was originally discovered at Tanabe Seiyaku (now Mitsubishi Tanabe). JW Pharmaceutical (previously Choongwae Pharma) and VIVUS have since developed and launched avanafil, which is an oral PDE5 inhibitor for the treatment of erectile dysfunction (ED). Although many marketed PDE5 inhibitors (e.g. sildenafil, vardenafil and tadalafil) are available for the treatment of ED, many patients are still unable to achieve the desired results and experience undesired side-effects with these existing medications. As such, second-generation PDE5 inhibitors with enhanced PDE5 selectivity, shorter systemic half-lives, and improved tolerability are desired. Developed to meet these criteria, Avanafil exhibited good oral bioavailability and PDE5 selectivity in both preclinical studies and clinical trials. Avanafil had a short onset of action (35 min) and short half-life (1.5 h).
SynthesisThe synthesis presented is based on the published patent procedure and is outlined in the scheme. Commercially available 4-chloro-2-(methylsulfanyl)pyrimidine- 5-carboxylic acid ethyl ester (25) was treated with 3- chloro-4-methoxybenzylamine (26) and triethylamine at room temperature to give 4-benzylaminopyrimidine derivative 27 in 96% yield. Sulfide 27 was then oxidized with m-chloroperbenzoic acid (m-CPBA), followed bytreatment with L-prolinol and triethylamine to afford ethyl pyrimidinate 28 in 83% yield. This ester was then saponified with 10% sodium hydroxide to give pyrimidine- 5-carboxylic acid 29 in 80% yield, which then underwent conventional amide bond formation using 2-(aminomethyl) pyrimidine (29a), N-(3-dimethylaminopropal)-N0-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole hydrate (HOBt) to give avanafil (IV) in 83% yield.

Synthesis_330784-47-9

Drug interactionsPotentially hazardous interactions with other drugs
Alpha-blockers: enhanced hypotensive effect - maximum dose 50 mg.
Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid; concentration increased by erythromycin - reduce avanafil dose; concentration reduced by rifampicin - avoid.
Antifungals: concentration increased by ketoconazole - avoid and fluconazole - reduce avanafil dose; concentration possibly increased by itraconazole and voriconazole - avoid.
Antivirals: concentration possibly increased by atazanavir, indinavir and saquinavir - avoid; concentration possibly reduced by efavirenz - avoid; concentration possibly increased by fosamprenavir - reduce avanafil dose; concentration significantly increased by ritonavir - avoid.
Aprepitant: concentration possibly increased by aprepitant - reduce avanafil dose.
Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - reduce avanafil dose.
Cobicistat: concentration of avanafil possibly increased - avoid.
Nicorandil: possibly enhanced hypotensive effect - avoid.
Nitrates: enhanced hypotensive effect - avoid.
Riociguat: possibly enhanced hypotensive effect - avoid.










MetabolismAvanafil is metabolised in the liver mainly by the cytochrome P450 isoenzyme CYP3A4 and to a minor extent by the CYP2C isoform. Two major metabolites are produced, one of which is active. Avanafil is excreted as metabolites mainly in the faeces (approximately 63%) in the urine (approximately 21%).
references[1] kotera j, mochida h, inoue h, noto t, fujishige k, sasaki t, kobayashi t, kojima k, yee s, yamada y, kikkawa k, omori k. avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. j urol. 2012 aug;188(2):668-74.
[2] cui ys, li n, zong ht, yan hl, zhang y. avanafil for male erectile dysfunction: a systematic review and meta-analysis. asian j androl. 2014 may-jun;16(3):472-7.
5-PYRIMIDINECARBOXAMIDE Guaiacol ALTRENOGEST POLY(ETHYLENE GLYCOL) METHYL ETHER ACRYLATE Methoxydiethylborane Anisole m-Anisyl alcohol (Trifluoromethoxy)benzene 6-Aminocaproic acid Glycine Difluorochloromethane p-Anisidine Methoxyacetic acid p-Anisaldehyde Tris(hydroxymethyl)aminomethane AMINO ACIDS 3-Aminophenol Avanafil

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