Description
Summary Abstract
Aminotadalafil (Amino-tadalafil; RR-ATDF; CAS 385769-84-6) is a synthetic analog of tadalafil with an additional primary amine substituent at the 6-position of the piperazinedione ring, yielding the molecular formula C21H18N4O4 (MW 390.39 g/mol). Like tadalafil, aminotadalafil is a potent inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for hydrolysis of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells. By preventing cGMP degradation, PDE5 inhibition sustains the vasodilatory signaling cascade initiated by nitric oxide (NO), producing relaxation of smooth muscle in penile corpora cavernosa, pulmonary vasculature, and lower urinary tract. As a research analog, aminotadalafil is employed to characterize PDE5 inhibitor pharmacology, probe structure-activity relationships within the tadalafil scaffold, and investigate cGMP-mediated signaling in cardiovascular and urological research contexts.
Clinical Indications
Aminotadalafil’s PDE5 inhibitory mechanism supports investigation in the following research contexts:
- Erectile Function and Penile Hemodynamics: PDE5 inhibition in cavernosal smooth muscle sustains cGMP-mediated relaxation of the helicine arteries and sinusoidal spaces, increasing blood flow and intracavernosal pressure; aminotadalafil provides a structural variant for SAR studies within this pharmacological class.
- Pulmonary Arterial Hypertension (PAH) Research: PDE5 is highly expressed in pulmonary vascular smooth muscle; cGMP-mediated vasodilation via PDE5 inhibition is the basis of approved PAH pharmacotherapy, and aminotadalafil supports investigation of structural modifications affecting pulmonary vascular selectivity.
- Lower Urinary Tract and Smooth Muscle Studies: PDE5 expression in bladder detrusor and prostatic smooth muscle supports use of PDE5 inhibitors in benign prostatic hyperplasia (BPH) research models; the aminotadalafil scaffold enables comparative pharmacological characterization.
Contraindications
- Nitrate Co-administration: PDE5 inhibitors markedly potentiate the hypotensive effects of organic nitrates through synergistic cGMP elevation; any research protocol using nitric oxide donors or nitrate compounds alongside aminotadalafil requires stringent hemodynamic monitoring.
- Potent CYP3A4 Modulators: The tadalafil scaffold is metabolized by CYP3A4; strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) or inducers may significantly alter aminotadalafil exposure and should be accounted for in multi-drug experimental designs.
- Cardiovascular Instability Models: PDE5 inhibition produces systemic vasodilation; in models with baseline hypotension, severe left ventricular outflow obstruction, or retinitis pigmentosa-related PDE6 concerns, hemodynamic and visual endpoints should be specifically monitored.
Mechanism of Action (MOA)
Aminotadalafil inhibits PDE5 to sustain cGMP-mediated smooth muscle relaxation through the NO/cGMP/PKG axis:
PDE5 Inhibition
Aminotadalafil competitively occupies the catalytic site of PDE5 (phosphodiesterase type 5), preventing the hydrolysis of cGMP (cyclic guanosine monophosphate) to 5′-GMP. PDE5 is the predominant cGMP-hydrolyzing enzyme in vascular smooth muscle cells of the corpora cavernosa and pulmonary vasculature; its inhibition prolongs elevated intracellular cGMP concentrations initiated by endogenous NO release.
PKG Activation and Smooth Muscle Relaxation
Sustained elevated cGMP activates protein kinase G (PKG), which phosphorylates myosin light-chain kinase and activates K⁺ channels, reducing cytosolic Ca²⁺ and inhibiting smooth muscle contraction. This cascade produces vasodilation of smooth muscle in cavernosal tissue, pulmonary arteries, and the lower urinary tract, directly mediating the downstream physiological effects of aminotadalafil.
Selectivity and the Primary Amine Modification
The 6-amino substituent in aminotadalafil introduces an additional hydrogen-bond donor/acceptor at a position proximal to the PDE5 catalytic site. This modification alters the compound’s binding geometry and pharmacokinetic profile relative to tadalafil, making aminotadalafil a valuable tool for structure-activity relationship (SAR) studies probing how modification of the piperazinedione scaffold affects PDE5 binding affinity, selectivity over PDE6/PDE11, and physicochemical properties relevant to formulation.
Key Features & Specifications
Aminotadalafil is employed as a structural analog for PDE5 pharmacology and cGMP pathway research:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | (2R,8R)-6-amino-2-(1,3-benzodioxol-5-yl)-3,6,17-triazatetracyclo[8.7.0.0³,⁸.0¹¹,¹⁶]heptadeca-1(10),11,13,15-tetraene-4,7-dione |
| CAS Number | 385769-84-6 |
| Molecular Formula | C21H18N4O4 |
| Molecular Weight | 390.39 g/mol |
| PubChem CID | available via CAS 385769-84-6 |
| Synonyms | Amino-tadalafil, RR-ATDF, Aminotadalafil |
| Form / Variation | 5 MG Capsules (SKU C-026) / 20 MG/mL Liquid 30 mL (SKU L-016) |
Storage, Safety, and Handling
Storage Protocol
Store capsule form at −20 °C in a sealed container, dry and protected from light. The liquid formulation (20 mg/mL) should be stored at −20 °C; once thawed for use, maintain at 4 °C and use within the manufacturer’s indicated window. Aminotadalafil is insoluble in water and ethanol; DMSO stock solutions (≥57.4 mg/mL) are stable at −20 °C when sealed and light-protected.
Handling & Compliance
Handle with standard laboratory PPE. Aminotadalafil is a PDE5 inhibitor structural analog; its pharmacological activity in systemic absorption scenarios is anticipated to be similar to tadalafil. Researchers handling the compound should avoid unintended dermal or oral exposure. The compound is not FDA-approved for any therapeutic indication and is supplied as an investigational research material.