PDE5 (IC50 = 90 nM)

PDE5 is inhibited by cis-tadalafil (compound 12b) at an IC50 of 0.09 μM [1].

Interactions
Concomitant use of antacids (magnesium hydroxide/aluminum hydroxide) and tadalafil reduces the apparent absorption of tadalafil but does not alter the tadalafil exposure (AUC). A significant interaction between tadalafil and nitroglycerin has been observed, lasting up to 48 hours; tadalafil should be taken at least 48 hours before considering nitrates. Tadalafil is contraindicated in patients who are regularly or intermittently using any form of organic nitrates; clinical pharmacology studies have shown that tadalafil enhances the hypotensive effect of nitrates; this is believed to be due to the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. The safety and efficacy of tadalafil in combination with other medications for erectile dysfunction have not been studied; combination use is not recommended. For more complete data on interactions of tadalafil (15 in total), please visit the HSDB records page.

[1]. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem. 2003 Oct 9;46(21):4533-42.

Modification of the hydantoin ring in the previously described lead compound 2a led to the discovery of compound 12a, tadalafil, a highly potent and selective PDE5 inhibitor. Substituting the hydantoin ring in compound 2a with a piperazine dione ring yielded compound cis-11a, which exhibits similar PDE5 inhibitory activity to 2a. Introducing a 3,4-methylenedioxy group at the 6-position of the benzene ring resulted in cis-11c, a highly potent PDE5 inhibitor with enhanced cellular activity. Chain optimization on the piperazine dione ring identified the racemic cis-N-methyl derivative 11i. The piperazine dione series of compounds exhibits high diastereoselectivity for PDE5 inhibition, with the cis-(6R,12aR) enantiomer showing the highest PDE5 inhibitory activity. Piperazine dione compound 12a, namely tadalafil (GF196960), has been proven to be a potent PDE5 inhibitor (IC50 = 5 nM), with significantly higher selectivity for PDE5 than for PDE1-4 and PDE6. Compound 12a exhibits 85 times higher selectivity for PDE6 than sildenafil. In a spontaneously hypertensive rat model, oral administration of 12a (5 mg/kg) resulted in a significant and sustained decrease in blood pressure (30 mmHg reduction over 7 hours).

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Therapeutic Use
Tadalafil is indicated for the treatment of erectile dysfunction. /Included in US Product Labelling/

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Drug Warnings
The US Food and Drug Administration (FDA) has approved updated labels for Cialis, Levitra, and Viagra to reflect a small number of post-marketing reports of sudden vision loss. These sudden vision losses are attributed to non-arteritis-ischemic optic neuropathy (NAION), a condition that obstructs blood flow to the optic nerve. The FDA recommends that patients experiencing sudden vision loss or decreased vision in one or both eyes should immediately stop taking these medications and contact their doctor or healthcare provider. Furthermore, patients currently taking or considering these products should inform their healthcare professional if they have experienced severe vision loss (which may reflect a previous occurrence of NAION). Such patients are at higher risk of recurrence of NAION. Because sexual activity carries certain risks, a patient's cardiovascular condition should be considered; men who are unable to engage in sexual activity due to underlying cardiac conditions should not use medications for erectile dysfunction, including tadalafil. The following cardiovascular disease patient groups were not included in clinical safety and efficacy trials of Cialis, and therefore, Cialis is not recommended for these groups until more information is available: patients who have had a myocardial infarction within the past 90 days; patients with unstable angina or angina during intercourse; patients with heart failure classified as NYHA class 2 or higher within the past 6 months; patients with uncontrolled arrhythmias, hypotension (<90/50 mmHg), or uncontrolled hypertension (>170/100 mmHg); and patients who have had a stroke within the past 6 months. Furthermore, patients with known hereditary retinal degenerative diseases (including retinitis pigmentosa) were not included in clinical trials, and this product is not recommended for such patients. In a randomized, double-blind, placebo- and active-drug (IVIG) controlled crossover study, researchers evaluated the effect of a single 100 mg dose of tadalafil on the QT interval at peak plasma concentration in 90 healthy men aged 18 to 53 years. Compared with placebo, the mean change in QTc (Fridericia QT corrected) in the tadalafil group was 3.5 ms (two-sided 90% confidence interval = 1.9, 5.1). Compared with placebo, the mean change in QTc (individual QT corrected) in the tadalafil group was 2.8 ms (two-sided 90% confidence interval = 1.2, 4.4). The 100 mg tadalafil dose (5 times the highest recommended dose) was chosen because this dose covers the exposure observed when tadalafil is used in combination with a potent CYP3A4 inhibitor or in patients with renal impairment. In this study, the mean increase in heart rate after taking this dose of tadalafil was 3.1 beats/min compared with placebo.
For more complete data on drug warnings for tadalafil (18 in total), please visit the HSDB record page.

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Pharmacodynamics
Tadalafil exerts its therapeutic effect on erectile dysfunction by increasing the relaxation of penile stimulation-dependent smooth muscle, thereby promoting penile engorgement and erection. Relaxation of pulmonary vascular smooth muscle helps dilate blood vessels in patients with pulmonary hypertension, thus lowering pulmonary artery blood pressure. In benign prostatic hyperplasia (BPH), tadalafil may help reduce smooth muscle cell proliferation, thereby shrinking prostate volume and relieving anatomical obstruction causing urinary symptoms in BPH. Compared to other PDE5 inhibitors, tadalafil has a lower affinity for PDE6, which may explain its lower incidence of visual side effects.

C22H19N3O4

389.40396

389.138

C, 67.86; H, 4.92; N, 10.79; O, 16.43

171596-27-3

Nortadalafil;171596-36-4;Tadalafil;171596-29-5;ent-Tadalafil;629652-72-8;cis-ent-Tadalafil;171596-28-4;cis-Tadalafil-d3;1329799-70-3;cis-ent-Tadalafil-d3

9821704

Typically exists as solid at room temperature

1.51±0.1 g/cm3 (20 ºC 760 Torr)

295-296 ºC

2.087

1

4

1

29

702

2

CN1CC(=O)N2C(C1=O)CC3=C(C2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36

WOXKDUGGOYFFRN-IIBYNOLFSA-N

InChI=1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1

(6R,12aS)-6-(1,3-Benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino(1',2'

Tadalafil specified impurity A, 171596-27-3; Tadalafil, (6R ,12aS)-; cis-Tadalafil; Tadalafil 6R ,12as diastereomer; (-)-Tadalafil 6R ,12as diastereomer; CHEMBL139028; E319TQ0B6R; Tadalafil EP Impurity A; Tadalafil (6R ,12aS)- Tadalafil (6R ,12aS)- Lilly

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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