Benzyl Sildenafil (N-Benzyl Sildenafil, CAS 1446089-82-2, C₂₉H₃₆N₆O₄S, MW ~564.70 g/mol) is a structural analog of sildenafil (Viagra) belonging to the pyrazolo[4,3-d]pyrimidin-7-one class of PDE5 inhibitors. It is formally derived from sildenafil by replacing the N1-methyl group (-CH₃) with a benzyl substituent (-CH₂C₆H₅) while preserving the rest of the sildenafil scaffold — the 2-ethoxyphenyl group at C5, the 4-methylpiperazin-1-yl-sulfonyl moiety at the 5′-position, and the 3-propyl group on the pyrazole ring all remain unchanged. This single N1 substitution has several pharmacological consequences: (1) PDE5 Potency — the benzyl group introduces additional steric bulk into the N1-proximal hydrophobic cleft of PDE5 (formed by Tyr664, Leu804, Val782), slightly reducing potency to IC₅₀ ~5-15 nM vs sildenafil’s ~3-5 nM; (2) Isozyme Selectivity — the N1 aromatic substituent interacts differently with non-conserved residues across PDE isozymes, altering PDE5/PDE6 and PDE5/PDE11 selectivity ratios; (3) Pharmacokinetics — increased lipophilicity (logP ~3.8 vs ~2.7) affects absorption, distribution, plasma protein binding, and CYP3A4-mediated hepatic clearance, while the benzylic methylene linker (-CH₂-) creates a site for oxidative metabolism not present in sildenafil; (4) Analytical Signature — with [M+H]⁺ at m/z ~565.3 (90 Da heavier than sildenafil’s m/z 475.2) and a distinct CID fragmentation pattern, Benzyl Sildenafil is identifiable within multi-analyte adulterant screening methods. Critical regulatory note: Benzyl Sildenafil is NOT an FDA-approved drug; it has NOT undergone clinical safety or efficacy testing; and its presence in any consumer product constitutes illegal adulteration. It is provided by UPOR Biotech exclusively as a Research Use Only (RUO) reference standard for analytical testing and laboratory research applications.

Benzyl Sildenafil is one of the most frequently detected undeclared synthetic PDE5 inhibitor analogs in adulterated dietary supplements and “herbal” sexual enhancement products worldwide. Its use as a certified reference standard is driven by several converging factors: (1) Prevalence in the adulterated product marketplace — since approximately 2012, Benzyl Sildenafil has been repeatedly identified in seized products by FDA, EMA, TGA, Health Canada, Interpol, and national customs agencies. It is a member of the “sildenafil analog family” — over 80 structurally modified PDE5 inhibitors deliberately designed to evade regulatory detection while retaining pharmacological activity. (2) Distinct analytical signature — Benzyl Sildenafil produces a characteristic mass spectrometric profile: [M+H]⁺ precursor ion at m/z ~565.3 with CID product ions at m/z ~489 (benzyl loss), m/z ~419, m/z ~393, m/z ~331, m/z ~282, and m/z ~112 (4-methylpiperazine). This unique fragmentation pattern, combined with a distinct reversed-phase HPLC retention time, enables unambiguous identification even in complex botanical matrices that contain hundreds of co-extracted compounds. (3) Non-natural origin — Benzyl Sildenafil is a fully synthetic compound with no known natural source. Any detection at any concentration is definitive evidence of deliberate adulteration — there is no “natural occurrence” defense that a supplement manufacturer could invoke. (4) Regulatory mandate — FDA, EMA, and equivalent agencies require ISO/IEC 17025 accredited laboratories to use authenticated certified reference materials for quantitative analysis. A properly characterized reference standard (with HPLC purity, 1H-NMR structural confirmation, HRMS exact mass, qNMR traceability) is the foundation of legally defensible adulteration testing. (5) Evolving adulterant landscape — as regulatory agencies add specific analogs to targeted screening lists, illicit manufacturers create new structural variants. Maintaining a comprehensive library of characterized analog reference standards — including Benzyl Sildenafil — is essential for staying ahead of this “analog-by-design” evasion strategy. UPOR Biotech’s Benzyl Sildenafil reference standard supports the development and validation of LC-MS/MS, LC-QTOF, and GC-MS methods for multi-residue PDE5 inhibitor screening in dietary supplements, enabling laboratories to protect consumer safety and meet regulatory compliance obligations.

The N1-benzyl substitution on the sildenafil scaffold provides critical structure-activity relationship (SAR) data for PDE5 inhibitor drug discovery, illustrating how even a single substituent change modulates multiple pharmacological parameters. Key SAR insights include: (1) N1 Steric Tolerance — the pyrazolo[4,3-d]pyrimidin-7-one core tolerates a benzyl group at N1 while retaining low nanomolar PDE5 potency (IC₅₀ ~5-15 nM), confirming that the N1-proximal hydrophobic cleft in PDE5 (defined by Tyr664, Leu804, and Val782) can accommodate larger aromatic substituents beyond the methyl group of sildenafil. This SAR finding has been exploited in the design of second- and third-generation PDE5 inhibitors, including avanafil, which uses a pyrimidinylmethyl substituent at the equivalent N-position. (2) Isozyme Selectivity Modulation — the benzyl group alters the inhibitor’s selectivity fingerprint across the 11-member PDE superfamily. The N1 substituent interacts directly with non-conserved residues lining the PDE5 binding pocket; larger aromatic N1 groups can improve PDE5/PDE6 selectivity (reducing the visual side effects — cyanopsia, photophobia — caused by PDE6 inhibition in retinal photoreceptors) while potentially altering PDE5/PDE11 cross-reactivity (PDE11 is expressed in skeletal muscle, pituitary, and testis). Comparative selectivity profiling of N1-benzyl vs N1-methyl (sildenafil) analogs enables rational optimization of the PDE5 selectivity window. (3) Binding Kinetics — Residence Time — the steric and hydrophobic character of the N1 substituent affects the inhibitor’s off-rate (k_off) from PDE5. A benzyl group, with greater hydrophobic contact surface area than a methyl group, can increase residence time (longer target engagement), potentially extending duration of action — a parameter of significant interest in PDE5 inhibitor design where tadalafil’s extended half-life (17.5 hours) is a key clinical differentiator. (4) Metabolic Stability — the N1-benzyl group introduces a benzylic methylene (-CH₂-) that is susceptible to CYP450-mediated oxidation, potentially generating benzyl alcohol and N-debenzylated (desbenzyl) metabolites. This contrasts with sildenafil’s N1-methyl, which undergoes N-demethylation at the piperazine ring (major metabolite: N-desmethyl sildenafil, UK-103,320). Understanding N1 substituent metabolism guides analog design toward metabolically stable substituents (e.g., using fluorinated or heterocyclic N1 groups) for improved pharmacokinetics. (5) Water Network Disruption — crystallographic studies of PDE5-inhibitor complexes have identified structured water networks in the binding pocket. The N1 benzyl group displaces water molecules differently than the N1 methyl, altering the enthalpic and entropic contributions to binding free energy — a nuanced SAR variable that computational chemistry approaches (FEP, WaterMap, 3D-RISM) can exploit for binding affinity prediction. Collectively, these SAR insights make Benzyl Sildenafil a valuable comparator compound in PDE5 inhibitor medicinal chemistry programs, demonstrating how the N1 position serves as a tunable handle for optimizing potency, selectivity, pharmacokinetics, and duration of action.

UPOR Biotech supplies Benzyl Sildenafil in two purity grades, each with a documentation package tailored to its intended use: Research Grade (≥98% HPLC) — suitable for analytical method development, preliminary dietary supplement screening, academic PDE5 pharmacology research, and in-house reference standard library construction. Documentation includes: COA with HPLC purity (≥98.0%, area normalization at 254 or 292 nm), related substances/impurity profile, water content (KF), and residual solvent analysis (GC-HS per USP <467>); MSDS; signed and dated HPLC chromatogram with peak purity analysis (PDA); 1H-NMR spectrum (400 or 500 MHz, in DMSO-d₆ or CDCl₃, with peak assignments confirming N1-benzyl substitution); HRMS report (ESI-QTOF, exact mass measurement, isotopic pattern matching confirming C₂₉H₃₆N₆O₄S molecular formula); FT-IR spectrum (ATR, confirming pyrazolopyrimidinone carbonyl stretch, sulfonamide S=O stretches, aromatic C=C); Certificate of Origin; and RUO disclaimer. Reference Standard Grade (≥99% HPLC) — intended for validated quantitative analytical methods (LC-MS/MS calibration curves, matrix-matched standards), pharmaceutical impurity quantification in sildenafil API, regulatory compliance testing, forensic casework, and proficiency testing programs. Includes all Research Grade documentation plus: COA with HPLC purity ≥99.0% and individual unspecified impurity ≤0.2%; sildenafil (N1-methyl analog) quantified as specified impurity at ≤0.3%; quantitative NMR (qNMR) purity value with uncertainty budget, traceable to SI units through a certified internal standard (e.g., 1,2,4,5-tetrachloro-3-nitrobenzene or dimethyl terephthalate, NIST-traceable); expanded elemental impurities report (ICP-MS, ICH Q3D); three-batch COA summary demonstrating inter-batch consistency; and accelerated stability data (40°C/75%RH, 6 months). Both grades are Research Use Only (RUO) — prominently labeled as NOT for human diagnostic or therapeutic use, NOT an FDA-approved drug substance, and NOT for compounding or formulation into any consumer product. Every shipment includes a signed RUO acknowledgment form. Free sample (typically 10-25 mg) available for qualified analytical laboratories, regulatory agencies, and academic research groups after evaluation of end-use statement. MOQ: 10 mg (Research Grade) / 25 mg (Reference Standard Grade). Competitive tiered pricing for bulk quantities (100 mg, 500 mg, 1 g). All documents provided in English.

UPOR Biotech maintains comprehensive quality management and manufacturing certifications supporting the supply of Benzyl Sildenafil and other research reference standards: ISO 9001:2015 Certification — quality management system covering design, development, production, and distribution of analytical reference standards and pharmaceutical impurities; c-GMP Compliance Statement — reference standard manufacturing conducted under current Good Manufacturing Practice principles with documented batch records, raw material traceability, equipment qualification (IQ/OQ/PQ), environmental monitoring, and change control; FDA Facility Registration — registered with the US FDA as a drug establishment; Complete Lot Traceability — every Benzyl Sildenafil lot is traceable from raw material sourcing through synthesis, purification, characterization, packaging, and shipment, with full batch manufacturing records and analytical data package archived for regulatory audit readiness; BSE/TSE-Free Statement — no animal-derived materials used in synthesis or processing; Residual Solvent Compliance — all lots tested for residual solvents per USP <467> / ICH Q3C / Ph. Eur. 5.4 guidelines; Elemental Impurities Compliance — all lots tested for Class 1, 2A, 2B, and 3 elemental impurities per ICH Q3D / USP <232>/<233>. For Benzyl Sildenafil specifically: a Research Use Only (RUO) Disclaimer is prominently displayed on all certificates, labels, and documentation. This product is: NOT for human or veterinary diagnostic use, NOT for therapeutic or prophylactic use, NOT an FDA-approved drug substance or drug product, NOT a dietary ingredient as defined by DSHEA (21 CFR 190.6), NOT intended for compounding or formulation into any product intended for human consumption or administration. It is solely intended for laboratory research, analytical method development and validation, forensic testing, and pharmaceutical impurity identification. UPOR Biotech reserves the right to decline orders from parties that cannot demonstrate legitimate analytical or research use. Shipping and logistics: Courier options include FedEx, DHL, UPS, or customer-specified carrier. Ambient temperature shipment in amber glass vials under argon atmosphere with PTFE-lined caps. Customs documentation: commercial invoice with HS code 2933.59 (compounds containing a pyrimidine ring), Certificate of Origin, and MSDS included. Lead time: 1-3 business days for in-stock items; 2-4 weeks for custom synthesis quantities. All documents provided in English; translation services available for regulatory submissions upon request. Contact UPOR Biotech for a detailed quotation, sample request, or technical discussion regarding your specific analytical requirements.