In corpus cavernosum strips from the diabetic group, avanafil (TA-1790) (0.01-1000 µM) increases the relaxation responses induced by electrical field stimulation (1-20 Hz) by 45%[2].

Avanafil (TA-1790) (10 mg/kg; po; daily, for 30 d; male rat) dramatically reduces oxidative stress, bone atrophy, and BMD loss caused by dexamethasone while also increasing angiogenesis in bone tissue through the activation of the NO, cGMP, and PKG (NO/cGMP/PKG) signaling pathway[1]. T2DM rats' erectile responses are improved by avanafil (TA-1790) (10 µM; ICI; once, for 10 weeks)[2].

Animal/Disease Models: Male rat model of glucocorticoid-induced osteoporosis (GIOP)[1]
Doses: 10 mg/kg
Route of Administration: Oral administration; daily, for 30 days
Experimental Results: diminished the level of eNOS, NO, PDE-5, PICP, MDA, CoQ10/CoQ10H and 8-OHdG/108dG. Increased the level of cGMP, PKG, Cortisol and CTCP.

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Animal/Disease Models: Male rat model of glucocorticoid-induced osteoporosis (GIOP)[1]
Doses: 10 mg/kg
Route of Administration: Oral administration; daily, for 30 days
Experimental Results: Increased right femur trabecular bone thickness and epiphyseal bone width.

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Animal/Disease Models: Male T2DM Sprague Dawley rats[2]
Doses: 10 µM
Route of Administration: Intracavernous injection; once, for 10 weeks
Experimental Results: Increased in ICP/MAP in response to nerve stimulation and increased total ICP values.

Absorption, Distribution and Excretion
Avanafil is rapidly absorbed following oral administration (Tmax of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in Tmax of 1.12 to 1.25 hours, a 39% mean reduction in Cmax, and a negligible effect on AUC.
Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine.
The apparent volume of distribution of avanafil is 47 to 83 L.

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Metabolism / Metabolites
Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil.

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Biological Half-Life
Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 hours.

Hepatotoxicity
Avanafil has had limited general use, but in premarketing studies it was not associated with cases of clinically apparent liver injury and serum enzyme elevations were not reported. The related PDE5 inhibitors, sildenafil and tadalafil, have been linked to isolated, rare instances of acute liver injury and jaundice. The latency to onset ranged from a few days to 3 months and the pattern of injury was usually cholestatic. Autoimmune and immunoallergic features were not observed and all cases were self-limited without residual injury or acute liver failure. Whether avanafil can cause a similar form of acute liver injury is not yet known.
Likelihood score: E* (unproved but suspected rare cause of clinically apparent liver injury).

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Protein Binding
Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%).

[1]. Effects of the Phosphodiesterase-5 (PDE-5) Inhibitors, Avanafil and Zaprinast, on Bone Remodeling and Oxidative Damage in a Rat Model of Glucocorticoid-Induced Osteoporosis. Med Sci Monit Basic Res. 2018 Mar 13;24:47-58.

[2]. The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dysfunction. Urology. 2014 Feb;83(2):508.e7-12.

[3]. Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. J Urol. 2012 Aug;188(2):668-74.

Avanafil is 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. It has a role as an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor and a vasodilator agent. It is a member of pyrimidines, an aromatic amide, an organochlorine compound, a member of prolinols and a monocarboxylic acid amide.
Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used in the treatment of erectile dysfunction. In comparison with other drugs of the same class, it shows greater selectivity for PDE5 over PDE6 than both [sildenafil] and [vardenafil] but less selectivity than [tadalafil], suggesting a relatively lower risk of visual disturbances associated with off-target PDE6 inhibition. It first received FDA approval on April 27, 2012, with subsequent EMA approval in June 2013.
Avanafil is a Phosphodiesterase 5 Inhibitor. The mechanism of action of avanafil is as a Phosphodiesterase 5 Inhibitor.
Avanafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) and is used as therapy of erectile dysfunction. Avanafil is a relatively new medication and has yet to be linked to instances of serum enzyme elevations or with clinically apparent acute liver injury.
Avanafil is an orally available phosphodiesterase type 5 (PDE5) inhibitor with vasodilatory activity. Avanafil selectively inhibits PDE5, thus inhibiting the degradation of cyclic guanosine monophosphate (cGMP) found in the smooth muscle of the corpus cavernosa of the penis. The inhibition of cGMP degradation results in prolonged muscle relaxation, vasodilation, and blood engorgement of the corpus cavernosa, thereby prolonging penile erection.

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Drug Indication
Avanafil is indicated for the treatment of erectile dysfunction.
FDA Label
Treatment of erectile dysfunction in adult men. In order for Spedra to be effective, sexual stimulation is required.

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Mechanism of Action
Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal.

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Pharmacodynamics
Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated _in vitro_ IC₅₀ of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as [sildenafil] and [vardenafil]. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy.

C23H26CLN7O3

483.95

483.178

330784-47-9

Avanafil dibenzenesulfonate;330784-48-0;(R)-Avanafil;1638497-26-3;Avanafil-13C,d3

9869929

White to off-white solid powder

1.4±0.1 g/cm3

150-152ºC

1.651

3.52

3

9

9

34

642

1

COC1=C(C=C(C=C1)CNC2=NC(=NC=C2C(=O)NCC3=NC=CC=N3)N4CCC[C@H]4CO)Cl

WEAJZXNPAWBCOA-INIZCTEOSA-N

InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1

(S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2pyrimidinylmethyl)-5-pyrimidinecarboxamide

TA 1790; TA1790; Avanafil; TA-1790; trade name: Stendra; Spedra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)