Structural–Functional Analysis of the Methoxy Group (–OCH₃) in Approved Small-Molecule Drugs: Mechanisms, Evidence Chains, and Product-Selection Navigation (with Related Product Tables)

Among 245 approved small molecules containing methoxy / fluorinated methoxy: a panoramic view of what –OCH₃ does—and what the evidence supports

The methoxy group (–OCH₃) is not a “decorative substituent.” Rather, it is a high-frequency structural “knob” that behaves like a lightweight module (adding only ~+31 Da) yet can simultaneously influence target binding, physicochemical properties, and metabolic fate. Its prevalence and effectiveness come from a simple structural fact: it bundles an oxygen atom (a potential H-bond acceptor / electronic tuner) and a methyl group (a small hydrophobic volume / pocket filler) into the smallest single substituent.

Why is this statement defensible? One of the strongest evidence anchors comes from the 2024 systematic review by Chiodi & Ishihara:

• The authors performed structural searches and curation across approved small-molecule drugs, collecting 245 drugs that contain methoxy or fluorinated methoxy (fluorinated methoxy) motifs.
• Within these 245 drugs, the review notes that the majority (>170; >70%) have sufficient SAR data, mechanistic studies, and/or X-ray co-crystal structural information, enabling the structural–functional role of methoxy to be assigned and discussed with relatively clear attribution.
• The authors also caution that for natural-product-derived drugs, the lack of strict matched molecular pairs (MMPs) or systematic substitution controls can make the precise contribution of methoxy harder to isolate.

Primary reference review:

• Chiodi, Debora; Ishihara, Yoshihiro. The role of the methoxy group in approved drugs. European Journal of Medicinal Chemistry. 2024; 273: 116364. (Epub 2024-04-04; Issue date 2024-07-05) DOI: 10.1016/j.ejmech.2024.116364; PubMed PMID: 38781921.

This review provides a clear starting point: in marketed drugs, methoxy is not an “accidental occurrence,” but a repeatedly deployed interpretable module.

1.Background and “development history”: Why does methoxy appear so frequently in drugs?

1.1 First layer: Natural products give methoxy an “inborn advantage”

• Many natural-product scaffolds inherently carry –OCH₃. This reflects biosynthetic diversification driven by O-methyltransferases, which O-methylate sites such as phenolic hydroxyls, thereby changing molecular polarity, volatility, membrane permeability, and interaction patterns. The more important natural products are as drug sources or inspirations, the more frequently methoxy appears in medicinal chemistry space.

1.2 Second layer: Synthetic accessibility enables parallel SAR scanning and rapid iteration

From a practical medicinal chemistry standpoint, –OCH₃ is a controllable, reversible, and systematically scannable substituent:

• Easy to install: Mature routes exist to introduce methoxy (etherification, nucleophilic substitution, metal-catalyzed coupling followed by methoxylation, etc.).
• Easy to vary: Within a series, it is straightforward to build parallel analogs such as H / Me / OMe / OH / F / CF₃, facilitating MMP (matched molecular pair) analysis—changing only one “part” to more cleanly read out the contribution of a substituent to activity and properties.
• Easy to rationalize: –OCH₃ brings two “visible” contributions: the oxygen often maps to structure- or mechanism-capturable H-bond acceptor/electronic effects; the methyl contributes a small hydrophobic volume that often improves van der Waals complementarity in a hydrophobic pocket (i.e., “filling a gap”). Because both contributions are frequently verifiable by SAR and co-crystal structures, reviews can often discuss methoxy’s role with relatively high confidence.

1.3 Third layer: From “empirical substitution” to the era of structural evidence

Over recent decades, the evidence base for drug design has shifted structurally:

• More systematic SAR (more substitution controls within a series);
• Wider adoption of structural biology (richer protein–ligand structural data; e.g., extensive “drug–target” X-ray co-crystals accumulated in PDB, the Protein Data Bank; the review explicitly used PDB to retrieve and curate structural evidence);
• Stronger ADME/metabolism evidence (ADME: Absorption–Distribution–Metabolism–Excretion; with more clinical and pharmacogenomic research, inter-individual variability, drug–drug interactions, and active-metabolite mechanisms are revealed more frequently and more systematically).

2.Definitions and structural features: What kind of “module” is MeO–?

2.1 Clarify the structure first: a “binary module”

Methoxy is –O–CH₃. Its key feature is duality: the smallest substituent that simultaneously bundles one polar point and a small hydrophobic volume:

• Oxygen (O): Typically acts as an H-bond acceptor (HBA) (note: methoxy generally does not donate H-bonds because it has no hydrogen to donate). It also introduces local polarity and tunes neighboring reactivity/binding preferences via electronic effects (on an aromatic ring, often an overlay of resonance donation (+M) and inductive withdrawal (–I)).
• Methyl (CH₃): Provides a small hydrophobic surface/volume, often improving van der Waals complementarity in a hydrophobic pocket—more plainly, it can “fill” a small gap that otherwise prevents tight fit, potentially increasing affinity or shifting selectivity.

Because a single substituent can deliver both a polar anchor and hydrophobic packing, methoxy is often treated as a lightweight but multifunctional tuning knob: minimal mass increase, yet potentially coupled effects across binding, properties, and metabolism.

2.2 Three “structural languages” of methoxy

Structural language	How to interpret it	Evidence handles
Interaction language	Methoxy oxygen as an HBA; methyl provides hydrophobic packing (fills a small hydrophobic void, increases van der Waals contacts)	① X-ray/cryo-EM co-crystal structures (PDB): directly see whether O forms an H-bond/water network, and whether CH₃ occupies a hydrophobic pocket; ② Strict SAR/MMP: only swap OMe ↔ H/Me/OH and observe activity/selectivity “jumps”; ③ Biophysical assays (ITC/SPR/thermal shift, etc.) supporting binding changes; ④ Computation/docking only as supporting interpretation
Electronic language	On aromatic rings, often an overlay of resonance donation (+M) and inductive withdrawal (–I), affecting local reactivity, pKa, and recognition preferences	① pKa/ionization fraction and property data (compare OMe ↔ H/Me/OH); ② Series SAR trends consistent with Hammett/substituent parameters; ③ Metabolic site/reactivity shifts (e.g., increased O-demethylation propensity or shifted oxidation sites); ④ Calculated charge/ESP maps as intuitive visuals (auxiliary evidence)
Conformational language	Methoxy can shift torsions/conformational populations. Gauche/anomeric effects are more common in aliphatic chains/adjacent heteroatom systems; for typical Ar–OCH₃, differences often come from ortho sterics → torsion changes and water/solvation network rearrangements.	① NMR conformational evidence (NOE, J couplings, VT-NMR, etc.) or crystal structures; ② MD/DFT conformational energy differences (should correspond to experiments); ③ Conformation locking in co-crystals (stronger when paired with a no-OMe control)

3.“Four main effects”: Four classes of visible outcomes methoxy delivers in marketed drugs

Main effect	What “quantifiable changes” you may observe	Practical value in drug R&D	Common misconceptions / boundaries
A. Binding & selectivity (pocket matching / interaction optimization)	Affinity/potency shifts: K_D, K_i, IC₅₀/EC₅₀; selectivity-window changes: fold-selectivity vs same-family targets; sometimes “remove OMe → activity drops sharply” in controls	Small change, big gain in potency or selectivity; especially useful when co-crystals or pocket knowledge exist (e.g., some kinases)	“Adding OMe always helps” is false—benefit depends on pocket geometry, water networks, and substitution position
B. Physicochemical properties & exposure (polarity/hydrophobic balance)	Property shifts: logP/logD, solubility, pKa, PSA; cell-level shifts: permeability/efflux (P-gp, etc.), effective intracellular concentration; in vivo shifts: AUC, Cmax, F (oral bioavailability)	Fine-tune developability without large mass increase; make exposure “more drug-like”	Solubility alone is not enough: solubility ↑ may mean permeability ↓; potency ↑ without sufficient exposure still fails
C. Conformation & 3D shape (pose bias / entropy cost)	Shifted conformational distributions: key dihedral preferences, conformer energy differences; more stable bound conformation (control compounds show “wrong/unstable pose”); sometimes selectivity/property differences at similar potency	Use “pose control” to reduce unproductive conformers and increase effective binding probability; sets up later selectivity optimization	Conformation is not mysticism—it requires “controls + evidence chain”; computation alone is rarely persuasive
D. Metabolic pathways & inter-individual variability (O-demethylation, etc.)	Metabolite shifts: demethylated products (phenols/hydroxyls); clearance/half-life shifts: CL, t½; changed fraction of active metabolites; genotype/DDI-driven differences in exposure/effects (e.g., CYP2D6-related)	Opportunity: prodrug/active-metabolite strategies; risk: variability, DDIs, underexposure, or safety liabilities	Don’t label O-demethylation as simply “good/bad”: it’s a double-edged sword—goal and context decide

4.Evidence chains from representative drugs: the “real contribution” of –OCH₃ in clinical medicines

Representative drug/scaffold (approved or core scaffold of an approved class)	Main area	The “key role” of methoxy	Authoritative reference
Codeine	Analgesic / antitussive	Metabolic switch / prodrug “cap”: 3-O-Me masks the phenolic OH, making the parent a weaker μ-receptor agonist; CYP2D6 O-demethylation → morphine markedly increases opioid activity, so efficacy and risk are highly sensitive to CYP2D6 activity (a classic approved-drug case where MeO determines the source of activity).	NCBI Medical Genetics Summaries: Codeine–CYP2D6 (explicitly identifies O-demethylation → morphine as a key step)
Tramadol	Analgesic	Metabolic switch / active-metabolite formation site: O-demethylation to M1 (O-desmethyltramadol) is a major route to stronger μ-receptor-related analgesic contribution; CYP2D6 inhibition or polymorphism alters M1 exposure and affects response/risk (“MeO site determines active-metabolite formation”).	FDA label: M1 formation depends on CYP2D6, is impacted by inhibition, and notes effects in different populations
Dextromethorphan (DXM)	Antitussive / CNS (also widely used as a metabolic phenotyping probe)	Metabolic switch / basis as a probe substrate: DXM O-demethylation → dextrorphan (DXO) is mainly mediated by CYP2D6; the DXM→DXO metabolic ratio is widely used to assess CYP2D6 activity, so the MeO site is the chemical basis for its use as a 2D6 probe.	DMD / review literature: CYP2D6-dominant O-demethylation to DXO and its use in phenotyping
Artemether	Antimalarial	Structural identity + in vivo bioactivation: It is itself a lactol methyl ether derivative; in vivo it can be metabolized to the major active metabolite DHA (dihydroartemisinin). Thus, MeO is both a “chemical identity label” and a key structural point shaping conversion/exposure profiles.	PubChem / ChEBI descriptions of structure and “metabolized to DHA”
Omeprazole	Gastrointestinal (PPI)	Electronic tuning element (supporting acid trapping/acid activation): PPI efficacy relies on enrichment/activation in strongly acidic environments; its pKa (especially pKa1 related to the pyridine N) determines ionization/trapping in parietal-cell acid. Omeprazole contains methoxy and related substituents as part of a substitution family used to tune pKa/activation behavior; multiple reviews discuss how substitution patterns (including methoxy/alkoxy) affect chemical stability and metabolic features, linking to developability differences.	PPI mechanism/chemistry reviews (pKa vs acid trapping; omeprazole pKa1); PPI reviews/overviews (substitution patterns including methoxy/alkoxy affecting activation reactivity and stability/metabolic differences)
4-Anilinoquinazoline (EGFR inhibitor family)	Oncology (kinases)	Pocket matching + SAR benchmark substitution pattern: 6,7-dimethoxyquinazoline is a classic high-performance motif in this family (e.g., PD153035: 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, with very steep SAR). The approved drug gefitinib retains a 7-methoxy and introduces a larger alkoxy side chain at C-6, reflecting a mature design syntax where MeO/alkoxy substituents act as well-developed “occupancy + electronic + conformational” tuning elements.	J. Med. Chem. 1996: PD153035 (6,7-dimethoxy) and steep SAR; PubChem provides gefitinib IUPAC including 7-methoxy

5.Conclusion

Methoxy is not decoration—it is an evidence-trackable structural knob

• At the binding level, methoxy often reshapes affinity and selectivity through “oxygen as an H-bond acceptor + methyl as hydrophobic packing.” Whether it helps depends on pocket geometry and water networks.
• At the properties level, methoxy is a compromise module between polarity and hydrophobicity: it does not add much mass, yet can markedly shift logD, solubility, permeability, and in vivo exposure—so it frequently appears in the critical final rounds of fine-tuning.
• At the metabolism level, the most typical fate is O-demethylation: it can create opportunities (active metabolites / controllable activation), but can also introduce faster clearance, variability, and DDI risk—this is the most important and most “must-pre-evaluate” double edge of MeO.

Practical reminder:

When you see –OCH₃ in papers or catalogs, instead of treating it as merely a “common substituent,” ask three questions first:

• Is it providing an interaction point, or is it filling pocket complementarity?
• Is it optimizing exposure/properties, or introducing a metabolic switch?
• If O-demethylation is involved: is that step the activation you want, or the clearance/variability source you must control?

Aligning these three questions with evidence (SAR, structures, ADME/metabolism) turns methoxy from “empirical substitution” into a testable design decision.

6. Product-Selection Navigation Table | Methoxy-Related Representative Drugs and Supporting Reagents (Tables 1–7)

Need / Scenario (typical research question)	Which table to check first	Why this table is the best fit	What you can quickly find in this table
Tumor mechanism validation / cytotoxic positive controls: need “phenotype-on-contact” standard drug controls for microtubules, Topo I/II, EGFR pathways, etc.	Table 1	Methoxy representative drugs: anti-tumor / targeted oncology	Consolidates the most commonly used anti-cancer functional control drugs, ideal for pathway causality validation, resistance/efflux studies, and dose–response curves
Anti-infective / susceptibility testing / resistance mechanisms: need representative drugs for DHFR, quinolones, TB inducers, etc., as positive controls or methodological standards	Table 2	Methoxy representative drugs: anti-infective / antiparasitic	Groups control drugs used in the same class of experiments (susceptibility, mechanism, PK), enabling “pick one workhorse control fast” for a given task
Neuro / psychiatry / sleep / cognition phenotypes: need standard controls for AChE inhibition, SSRI/SNRI, circadian rhythm, etc.; or need CNS stock preparation for cell/receptor assays	Table 3	Methoxy representative drugs: neuro / psychiatry / cognition (incl. anesthesia)	Summarizes classic CNS controls that can be used directly in cell/receptor/behavior readouts—suited for phenotype validation and PK/metabolism comparisons
Cardiovascular / metabolism / urology: sulfonylureas, calcium-channel blockers, β-blockers, α1 antagonists, antiplatelets—need “mechanism-matched lateral comparisons,” or DDI/transporter/metabolic phenotyping	Table 4	Methoxy representative drugs: cardiovascular / metabolism / urology / platelets	Aggregates clinically common—and also research-common—systemic controls by therapeutic area; best for parallel comparisons (same target/pathway) and assessing DDI/transporter impacts
Inflammation/analgesia / GI (PPIs) / photochemical controls: need COX inhibitors, PPIs (omeprazole/esomeprazole/rabeprazole), PUVA/photosensitizer controls; or need high-frequency “baseline controls” outside oncology/infection	Table 5	Methoxy representative drugs: GI / anti-inflammatory analgesia / photochemistry & other controls	Concentrates high-frequency baseline controls (PPIs, NSAIDs, photosensitizers, expectorants/prokinetics, etc.), ideal for routine pharmacology, mechanism work, and quantitative method development
LC/LC–MS method development, sample prep, stock-solution system building: concerned about background peaks/water/batch variation affecting quantitation of “methoxy → demethylated metabolite,” or need robust solvent systems for reproducible data	Table 6	Supporting chemicals: solvents & media (analytical/biological/reaction solvents)	Focuses on commonly used high-purity/anhydrous solvents to directly solve practical issues: “how to prepare samples,” “how to stabilize systems,” and “how to minimize background”
Use methoxy as a design knob for structural modification: e.g., demethylate Ar–OCH₃ to Ar–OH to prepare metabolites/controls; methylate –OH back for SAR controls; need ion pairs/strong bases/additives to drive reactions or derivatization	Table 7	Supporting chemicals: reaction aids & key reagents (bases/ion-pairs/demethylation/methylation/derivatization)	Directly maps to “how to make it / how to verify it” operations: one-stop locating demethylation, methylation, derivatization, and ion-pair/base systems

Table 1. Anti-Tumor / Targeted Oncology

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Representative drug | Antitumor / microtubule inhibitor	33069-62-4	P106868	Paclitaxel	Moligand™, analytical standard, ≥99%	Microtubule stabilizer: widely used as a positive control for cytotoxicity/mitotic arrest, and for resistance/transporter studies; low solubility—typically prepared in DMSO and the final DMSO concentration should be controlled; avoid repeated freeze–thaw cycles.
Representative drug | Antitumor / Topo I inhibitor	97682-44-5	I127961	Irinotecan	Moligand™, ≥99%	Common Topo I inhibitor in cell/animal tumor models; PK studies are often evaluated together with its active-metabolite pathway—pay attention to solution pH and stability; protect from light.
Representative drug | Antitumor / EGFR-TKI	184475-35-2	G125799	Gefitinib (ZD1839)	Moligand™, ≥99%	Common inhibitor for causality testing of EGFR signaling (EGFR–ERK/AKT); recommended to pair with orthogonal inhibitors/genetic tools; keep final DMSO concentration low.
Representative drug | Antitumor / EGFR-TKI	183321-74-6	E126633	Erlotinib	Moligand™, ≥98%	Forms an “orthogonal same-target control” with gefitinib for EGFR pathway causality and resistance mechanisms; pair with downstream readouts (p-ERK/p-AKT) and time-course designs.
Representative drug | Antitumor / anthracycline	56390-09-1	E122334	Epirubicin hydrochloride	Moligand™, ≥98% (HPLC)	Common in cytotoxicity and efflux-resistance models; intrinsically fluorescent, enabling uptake/efflux assays; protect from light; control solution stability and adsorption losses.
Representative drug | Antitumor / Topo II inhibitor	33419-42-0	E121713	Etoposide	Moligand™, ≥98%	Widely used as a positive control for DNA damage/cell-cycle arrest; suitable for mechanism validation (e.g., γH2AX) and efficacy–toxicity window comparisons; protect from light and keep dissolution conditions consistent.
Representative drug | Antitumor / anthracycline	20830-81-3	D609748	Daunorubicin	Moligand™	Common control in cytotoxicity and efflux-resistance models; intrinsically fluorescent for uptake/efflux readouts; protect from light and store cold; watch adsorption and solution stability.

Table 2. Anti-Infective / Antiparasitic

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Representative drug | Antimalarial / artemisinin derivative	71963-77-4	A107446	Artemether	Moligand™, analytical standard, ≥98%	Standard antimalarial model drug and PK quantitation reference; relatively sensitive to light/oxygen—protect from light and use promptly after preparation; can serve as a comparator when discussing methoxy-containing motifs in metabolic stability.
Representative drug | Anti-infective / antibacterial (DHFR)	738-70-5	T129928	Trimethoprim	Moligand™, ≥99%	DHFR inhibitor: common control for enzyme inhibition, resistance mechanisms, and susceptibility assays; contains polymethoxy aromatics—useful as a template for O-demethylation metabolism and polarity-tuning discussions.
Representative drug | Anti-infective / macrolide	81103-11-9	C129746	Clarithromycin	Moligand™, ≥98%	Antibacterial pharmacology control; also commonly used as a positive control for “metabolic-enzyme inhibition” in DDI studies (dose/time must be tightly controlled); watch solution stability and protect from light.
Representative drug | Anti-infective / fluoroquinolone	151096-09-2	M302962	Moxifloxacin	Moligand™, ≥98%	A classic “8-methoxy quinolone” scaffold: widely used in susceptibility/Topo-related assays; the methoxy site is useful for SAR and photo/oxidative-stability comparisons; protect from light and consider metal-ion effects.
Representative drug | Anti-infective / anti-TB (inducer)	13292-46-1	R105455	Rifampicin	Moligand™, ≥97%	Classic positive control for nuclear-receptor-mediated induction of metabolic enzymes/transporters (e.g., CYP3A-related studies); polymethoxy scaffold is also useful for comparing metabolic complexity; strongly photosensitive—handle under light protection.
Representative drug | Antimalarial / 8-aminoquinoline	90-34-6	P187973	Primaquine	Moligand™, ≥95%	Typical antimalarial control based on a 6-methoxy quinoline scaffold; often used in RBC-related safety/metabolism mechanism studies; photosensitive—follow institutional safety practices for research use.

Table 3. Neuro / Psychiatry / Cognition (Including Anesthesia)

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Representative drug | Neuropharmacology / transporter control	50-55-5	R101672	Reserpine	Moligand™, analytical standard, ≥99.5%	Often used as a positive control for LC–MS system performance/sensitivity and as a comparator in transporter-related (e.g., efflux) studies; polymethoxy scaffold makes it useful as a template for O-demethylated metabolite screening; store cold and protect from light.
Representative drug | Neuropsychiatry / antidepressant (metabolism probe)	93413-69-5	D337434	D,L-Venlafaxine	Moligand™, ≥98%	Classic substrate for “methoxy → O-demethylation” metabolic-chain studies (often used in phenotyping/inhibitor screening and LC–MS quantitation); the D/L mixture suits total-exposure studies—chirality questions require separate design.
Representative drug | Neuropsychiatry / SSRI (DDI control)	54739-18-3	F337893	Fluvoxamine	Moligand™, ≥98%	SSRI pharmacology control; also frequently used as a positive control in enzyme-inhibition/DDI studies (careful with concentration and exposure time); suitable as a metabolism comparator for methoxy-containing aromatics.
Representative drug | Neuroendocrine / sleep	73-31-4	M118674	Melatonin	Moligand™, ≥98%	Control for circadian rhythm and receptor agonism assays; contains a 5-methoxyindole scaffold—useful for O-demethylation and receptor-SAR comparisons; protect from light and control solvent background.
Representative drug | Neuro / Alzheimer’s	357-70-0	G125955	Galantamine	Moligand™, ≥98%	Control for AChE inhibition and cholinergic-pathway studies; can be paired with donepezil for side-by-side mechanism/potency comparisons; consider salt form, solubility, and cytotoxicity thresholds.
Representative drug | Neuro / Alzheimer’s	120014-06-4	D101734	Donepezil (free base)	Moligand™, ≥98%	AChE inhibitor commonly used in cell/enzyme controls and PD validation; “free base vs salt” strongly affects solubility and stock stability—standardize the form before experiments.
Representative drug | Anesthesia / analgesia (volatile)	76-38-0	M1437224	Methoxyflurane	≥98%	Reference for volatile anesthesia/analgesia and related metabolism/toxicology studies; highly volatile—use sealed sampling and good ventilation, and avoid concentration drift due to evaporation.

Table 4. Cardiovascular / Metabolism / Urology / Platelets

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Representative drug | Metabolism / antidiabetic (sulfonylurea)	10238-21-8	G127198	Glyburide (Glibenclamide)	Moligand™, ≥99%	Common in KATP-channel and pancreatic β-cell function assays; also used as an inhibitory control in transporter/biliary-excretion studies; relatively low solubility—ensure a stable, reproducible formulation.
Representative drug | Metabolism / antidiabetic (sulfonylurea)	93479-97-1	G129354	Glimepiride	Moligand™, ≥99%	Same-mechanism comparator to glyburide; suitable for comparing “same class, different substituents (incl. –OCH₃)” across receptor/channel and ADME differences; monitor dissolution and lot-to-lot consistency.
Representative drug | Metabolism / antidiabetic (sulfonylurea)	29094-61-9	G129980	Glipizide	Moligand™, ≥98%	Sulfonylurea antidiabetic control (glipizide): commonly used for KATP-related functional assays (β-cell insulin secretion stimulation control) and for PK/metabolism and quantitative methods (HPLC/LC–MS standards, matrix-effect evaluation, same-class comparisons).
Representative drug | Cardiovascular / calcium-channel blocker	52-53-9	V303890	Verapamil	Moligand™, ≥98%	Cardiovascular mechanism control; also frequently used as a positive control in cellular efflux/transporter assays; polymethoxy scaffold makes it a reference compound for “transport–metabolism coupling” studies.
Representative drug | Cardiovascular / antiarrhythmic	54063-53-5	P413331	Propafenone	Moligand™, ≥98%	Control for cardiac ion-channel/antiarrhythmic mechanism studies; a classic compound with prominent CYP-mediated metabolism (with a methoxy site), useful for DDI and metabolic-phenotyping comparisons.
Representative drug | Cardiovascular / β-blocker (metabolism probe)	51384-51-1	M335879	Metoprolol	Moligand™, ≥97%	One of the classic CYP2D6 phenotyping probe substrates; commonly used in O-demethylation/hydroxylation metabolism studies and LC–MS method validation; control matrix effects and internal-standard strategy.
Representative drug | Cardiovascular / αβ-blocker	72956-09-3	C123267	Carvedilol	≥98% (HPLC)	Cardiovascular pharmacology control; also used in transporter/metabolism-related DDI studies (contains aryloxy/methoxy motifs); watch effects arising from racemate composition and keep preparation consistent.
Representative drug | Urology / α1 antagonist	106133-20-4	T332203	Tamsulosin	Moligand™, ≥97%	Control for α1-receptor pharmacology and smooth-muscle models; contains aryloxy/methoxy motifs for substituent–affinity/metabolism comparisons; consider salt form and solubility.
Representative drug | Cardiovascular / antiplatelet (prodrug)	113665-84-2	M637412	Clopidogrel	≥97%	Use alongside sulfate/enantiomeric versions for “salt form / configuration–activity–stability” comparisons; suitable for prodrug activation and QC method development (impurities/degradation); protect from light and moisture (hydrolysis).
Representative drug | Cardiovascular / antiplatelet (chiral)	120202-66-6	S129544	(S)-(+)-Clopidogrel sulfate	≥98%	Chiral prodrug control for P2Y12 pathway/platelet function studies; prioritize enantiomeric salt when assessing stereochemistry–activity/metabolism differences; control hydrolytic stability, protect from light, and standardize solvent conditions.

Table 5. GI / Anti-Inflammatory Analgesia / Other Controls and Special-Purpose Uses

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Representative drug | Chiral tool / natural product alkaloid	130-95-0	Q431754	(–)-Quinine	Moligand™, for resolving racemates in synthesis	A classic resolving agent/reference for chiral resolution and enantiomeric-purity studies; can also serve as a metabolic/spectroscopic comparator for aryloxy/methoxy systems—pay attention to salt form and optical-rotation consistency.
Representative drug | Photochemistry / metabolic-inhibition control	298-81-7	M115185	8-Methoxypsoralen	Moligand™, analytical standard, ≥98%	Classic control for PUVA / photocrosslinking systems; also often used as a positive control in metabolism/enzyme-inhibition studies (methoxy-containing aromatic scaffold). Highly photosensitive—strictly protect from light during handling and storage.
Representative drug | NSAID / enantiomeric control	22204-53-1	S161049	(S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid	Moligand™, ≥99%	A typical chiral NSAID control (enantiomer/configuration–activity relationship); suitable as a reference substrate for assessing binding and metabolic risk (including O-demethylation) associated with methoxy-substituted aromatics.
Representative drug | NSAID / COX inhibitor	53-86-1	I106885	Indomethacin (NSC-77541)	Moligand™, ≥99%	Common control for COX inhibition and inflammatory-pathway studies; also frequently used as a comparator for metabolic stability and physicochemical properties in aryloxy/methoxy-substituted systems. Consider solubility and vehicle selection carefully.
Representative drug | GI system / PPI (chiral)	119141-88-7	S586538	Esomeprazole	Moligand™, ≥99%	Common control for PPIs and for CYP2C19-related PK/interaction studies; acid- and light-sensitive—prepare quickly using an appropriate solvent, store cold, and protect from light.
Representative drug | GI system / PPI (racemate)	73590-58-6	O118724	Omeprazole	Moligand™, ≥98%	A classic PPI control, also widely used in studies of CYP2C19-driven metabolic variability; acid- and light-sensitive—protect from light, keep cold, and process rapidly with suitable buffers/solvents.
Representative drug | GI system / PPI	117976-89-3	H172338	Rabeprazole	Moligand™, ≥97%	PPI control; together with omeprazole/esomeprazole enables “same mechanism, different metabolic features” comparisons. For acid-suppression and CYP-related studies, account for light/acid sensitivity and stock-solution stability.
Representative drug | Respiratory system / expectorant	93-14-1	G129215	Guaifenesin	Moligand™, ≥98%	Used as an expectorant pharmacology control and LC–MS methodological standard; contains aryl ether/methoxy motifs, useful for discussing “aryloxy–OCH₃” impacts on metabolism (demethylation) and solubility.
Representative drug | Neuro / muscle relaxant	532-03-6	M129197	Methocarbamol	Moligand™, ≥98%	Reference for muscle-relaxant pharmacology/safety controls and quantitative-method development; polymethoxy aromatics can support demethylated-metabolite screening and physicochemical comparisons—keep solvent systems consistent.
Representative drug | GI system / antiemetic & prokinetic	364-62-5	M124438	Metoclopramide	≥98%	Common control in D2-antagonism/5-HT-related mechanism studies and GI motility models; contains a methoxy benzamide motif and can be used as a comparator for demethylation metabolism and polarity tuning.

Table 6. Solvents and Media (Biological/Analytical Solvents + Reaction/Green Solvents)

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Analytical / sample & system solvent | high-purity alcohol	67-56-1	M116128	Methanol	For protein sequencing, ≥99.9%	A common solvent for LC/LC–MS sample preparation and mobile phases: higher-purity grades better support trace-impurity/metabolite quantitation; also used for extraction, protein precipitation, and dissolving polar compounds. Selection tips: prioritize low background, low UV/low metals, and lot-to-lot consistency.
Analytical / sample & system solvent | ultra-low water	75-05-8	A433541	Acetonitrile (ACN)	For DNA synthesis, H₂O ≤ 10 ppm	For high-demand LC–MS/UPLC mobile phases and sample dilution: low water content benefits moisture-sensitive systems and reproducibility; in “methoxy → demethylated metabolite” quantitation, it can reduce baseline drift and ghost-peak risk. Selection tips: prioritize ultra-low-water / low-UV-background grades.
Biological-assay solvent | high-solubility stock solvent	67-68-5	D103280	Dimethyl sulfoxide (DMSO)	Pharmaceutical grade, PharmPure™	Stock-solution solvent for cell/enzyme assays: many methoxy-aromatic drugs are relatively hydrophobic and often require DMSO stocks. Selection tips: pharmaceutical grade helps reduce impurity interference; control final DMSO %, and prevent moisture uptake that can shift effective concentration.
Reaction solvent | halogenated solvent (anhydrous)	75-09-2	D433565	Dichloromethane (DCM)	Anhydrous, ≥99.8%, contains 40–150 ppm pentene as stabilizer	Common solvent for deprotection and boron-halide demethylation systems; dissolves many methoxy-containing aromatic substrates well. Selection tips: anhydrous grade suits moisture-sensitive Lewis acids; stabilizer-containing products are common commercial forms—high-sensitivity analysis should consider potential background contributions.
Reaction solvent | strongly polar amide (anhydrous)	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous, ≥99.8%	Polar reaction medium for dissolving salts and polar substrates; frequently used in substitutions, couplings, salt formation/dissolution; commonly appears when building methoxy/aryl-ether derivatives. Selection tips: for moisture-sensitive and reproducible work, prioritize anhydrous grade; prolonged high-temperature conditions may increase side reactions/background impurities.
Green solvent / carbonate | reaction medium	616-38-6	D119695	Dimethyl carbonate (DMC)	Anhydrous, ≥99%	A candidate “milder/greener” solvent and potential methyl-source option: in some systems it can support methylation or serve as a carbonate transformation medium (method-dependent). Selection tips: if evaluating routes that “replace harsh methylating agents,” include as a screening option; for moisture-sensitive reactions, prefer anhydrous grade.

Table 7. Reaction Aids and Key Reagents

(Inorganic salts/bases/ion-pairing + strong bases + demethylation/deprotection + methylation/derivatization)

Category	CAS No.	Aladdin Cat. No.	Name	Specification / Purity	Product application & selection notes
Inorganic salt / additive | nucleophilic halide / ionic strength	7681-11-0	P433793	Potassium iodide (KI)	Anhydrous, high purity, reagent grade, ≥99%	Ion-pairing/nucleophilic promotion and analytical support: often used as an I⁻ source in halogenation/substitution controls or to adjust ionic strength; can serve as a halide source/promoter in certain derivatization/conversion systems. Selection tips: for moisture-sensitive reactions, prioritize anhydrous grade.
Base | mild inorganic base	584-08-7	P485463	Potassium carbonate (K₂CO₃)	Anhydrous, high purity, reagent grade, ≥99%	A common mild base for O-alkylation / forming methoxy derivatives (e.g., generating phenolates from phenols prior to installing –OCH₃); also used to neutralize acidic impurities. Selection tips: mild and broadly compatible; for moisture-sensitive systems, prioritize anhydrous grade.
Base | strong / highly reactive carbonate	534-17-8	C432848	Cesium carbonate (Cs₂CO₃)	purum p.a., ≥98% (T)	A stronger/more “active” carbonate base: often used to drive challenging O-alkylations (e.g., phenolate formation) to introduce methoxy-related substituents with suitable methyl sources. Selection tips: stronger than K₂CO₃ but more expensive; useful for condition screening at “difficult sites.”
Chromatography / ion-pair additive | complexing agent	17455-13-9	C124569	18-Crown-6	Ion-pair chromatography grade, ≥99% (GC)	Ion pairing / K⁺ complexation to increase salt solubility and anion “freedom”: can serve as an additive control in systems where alkali-metal salts participate (e.g., phenol → methoxy derivatization); ensure recovery and consistency. Selection tips: chromatography grade better supports analytical methods and low-background needs.
Chromatography / ion-pair additive | quaternary ammonium salt	311-28-4	T103715	Tetrabutylammonium iodide (TBAI)	Ion-pair chromatography grade	Ion-pair chromatography / phase-transfer additive: improves retention and peak shape for ionic analytes, or serves as a control additive in phase-transfer systems (relevant to salt forms/charge-state studies of methoxy-containing drugs). Selection tips: for analytical use, prioritize chromatography grade to reduce impurity peaks.
Base / alkoxide | methoxy source	124-41-4	S431653	Sodium methoxide solution	ACS, 0.5 M CH₃ONa in methanol (0.5N)	A standard MeO⁻ source: used in methoxy-related reactions (e.g., transesterification; certain substitution/elimination systems under basic conditions) and as a methodological control. Selection tips: solution form improves dosing and reproducibility; watch moisture uptake and strong-base safety.
Strong base / hydride | generate strong nucleophiles	7646-69-7	S110860	Sodium hydride (NaH)	60% dispersion in mineral oil	Strong base to generate alkoxides/phenolates (high hazard): may be used to convert –OH into a stronger nucleophile to drive O-alkylation when building methoxy/aryl-ether derivatives. Selection tips: highly reactive and moisture-sensitive; recommended only for experienced teams under strict safety and compliance controls.
Demethylation / deprotection | Lewis acid (aryl-ether demethylation)	10294-33-4	B431276	Boron tribromide (BBr₃)	High purity, reagent grade, ≥99%	Classic reagent for Ar–OCH₃ → Ar–OH demethylation (high hazard, strongly corrosive): used to prepare phenolic metabolites/controls from methoxy drugs/building blocks, or to build structure–activity/property comparators. Selection tips: strong demethylation power but substrate compatibility must be evaluated; strictly control moisture; rigorous PPE and compliance required.
Demethylation / deprotection | Lewis acid (solution)	10294-34-5	B139889	Boron trichloride (BCl₃)	1.0 M solution in p-xylene	Another Lewis-acid option for aryl-ether demethylation/deprotection: can be used for condition screening to prepare “methoxy → phenol” comparators (substrate-dependent). Selection tips: solution form improves dosing/reproducibility; still highly corrosive/hazardous—strict compliance required.
Demethylation / deprotection | Lewis acid (complex activation)	7446-70-0	A433484	Aluminum chloride (AlCl₃)	High purity, reagent grade, ≥99%	Lewis-acid-promoted activation/rearrangement/cleavage control: can be included as a condition-screening option in certain aryl-ether/methoxy-related transformations (route/substrate dependent). Selection tips: strong Lewis acid, moisture-sensitive; better for “method screening/control conditions,” mindful of side-reaction risk.
Demethylation / silyl halide reagent | iodosilane (high hazard)	16029-98-4	I100104	Trimethylsilyl iodide (TMIS)	≥97%, copper-stabilized	Often used to convert ethers/esters into more labile intermediates (can support demethylation-route screening): a methodological option for deprotection/functional-group interconversions related to methoxy motifs. Selection tips: highly reactive and moisture-sensitive; stabilized forms support storage consistency.
Demethylation / deprotection | activated leaving group (sulfonate ester)	80-48-8	M105176	Methyl p-toluenesulfonate (MeOTs)	Chemical pure (CP), ≥96%	Strong methylating / sulfonate-activation reagent (high hazard): can be used to build methoxy-related derivatives or as a “strong methylation condition” control; also useful for evaluating good-leaving-group installation. Selection tips: high reactivity and risk; only trained personnel under compliance; consult SDS and institutional rules.
Methylation | iodomethane (solution, high hazard)	74-88-4	I466403	Iodomethane solution	≥99%, 2.0 M in tert-butyl methyl ether	Common SN2 methylating agent: converts phenols/alcohols/thiols to methyl ethers/thioethers to build methoxy analogs/controls. Selection tips: solution form supports accurate dosing; high toxicity and volatility—use in a fume hood and follow strict procedures.
Methylation / leaving-group activation | sulfonate ester (high hazard)	66-27-3	M301750	Methyl methanesulfonate (MeOMs)	≥98%	Strong methylating agent / sulfonate ester (high hazard): may appear in building methoxy-drug derivatives or as a harsh-condition control. Selection tips: strong alkylation and high risk; prioritize safer alternatives when possible; if necessary, operate under strict compliance.
Methylation | sulfate ester (high hazard)	77-78-1	D465758	Dimethyl sulfate (DMS)	≥98%	Strong methylating agent (often carries sensitization/carcinogenicity warnings): used for harsh methylation or condition-screening controls (route-dependent). Selection tips: extremely high risk—not recommended as a routine first choice; only when necessary under robust safety systems.
Super-strong methylating agent | triflate ester (high hazard)	333-27-7	M100679	Methyl trifluoromethanesulfonate (MeOTf)	≥97%	Extremely strong methylating agent (“hard-condition” control): used for difficult-site methylation or mechanistic/control studies (substrate-dependent). Selection tips: very high reactivity and very high risk; only under strict protection/compliance and when truly necessary.
Super-strong methylating agent | oxonium salt (high hazard)	420-37-1	T106614	Trimethyloxonium tetrafluoroborate	≥96%	Strong methylating reagent (oxonium salt): suitable for methylation needs where alkyl halides are ineffective, or for condition screening (substrate-dependent). Selection tips: strong reactivity with safety risks; for screening, start small-scale and strictly follow SDS.
Methylation / derivatization | diazomethane alternative (high hazard)	18107-18-1	T140538	(Trimethylsilyl)diazomethane	2.0 M in hexanes	Common alternative for esterifying carboxylic acids/acidic groups: often used in metabolite analysis to derivatize acidic metabolites into GC/LC-friendlier forms (method-dependent). Selection tips: easier to manage than diazomethane but still high hazard; for analytical derivatization, verify blanks/background and reaction completeness.

Note: The above are Aladdin representative products. For additional specifications, please refer to the full product list at the end of the article, or search the Aladdin website by product name/CAS.

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