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CE-123
CE-123
CE-123
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CE-123
(S)-CE-123
Clinical data
Other names(S)-CE-123; S-CE-123
Legal status
Legal status
Identifiers
  • (S)-5-(benzhydrylsulfinylmethyl)-1,3-thiazole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC17H15NOS2
Molar mass313.43 g·mol−1
3D model (JSmol)
  • O=S(Cc1cncs1)C(c2ccccc2)c3ccccc3
  • InChI=1S/C17H15NOS2/c19-21(12-16-11-18-13-20-16)17(14-7-3-1-4-8-14)15-9-5-2-6-10-15/h1-11,13,17H,12H2
  • Key:VBBBWHDWYLUSEL-UHFFFAOYSA-N

CE-123, or as the active enantiomer (S)-CE-123, is an analog of modafinil, the most researched of a series of structurally related heterocyclic derivatives.[1][2][3] In animal studies, CE-123 was found to improve performance on tests of learning and memory in a manner consistent with a nootropic effect profile.[4][5][6][7] (S)-CE-123 has pro-motivational effects in animals, reverses tetrabenazine-induced motivational deficits, and could be useful in the treatment of motivational disorders in humans.[8][9]

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References

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CE-123

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from Grokipedia
CE-123, chemically known as 5-((benzhydrylsulfinyl)methyl), is a novel synthetic analogue of designed as a selective (DAT) inhibitor with enhanced affinity and specificity for DAT compared to modafinil and its enantiomers. It blocks dopamine reuptake (IC50 = 4.606 μM) while exhibiting negligible effects on serotonin (SERT) and norepinephrine (NET) transporters, potentially reducing off-target side effects associated with broader monoamine modulation. Preclinical studies in models have demonstrated CE-123's procognitive effects, including improved acquisition and retrieval in spatial tasks, as evidenced by increased reference indices and reduced latency in hole-board tests following daily administration. In attentional set-shifting paradigms, low doses (0.3–1.0 mg/kg) of the active (S)- enhance without increasing , unlike higher doses of R-modafinil. Chronic treatment in aged rats (10 mg/kg for 15 days) boosts , performance in novel operant tasks, and , such as cooperation in paired assays, suggesting potential benefits for age-related or dysfunction-related cognitive deficits. Pharmacokinetically, CE-123 readily crosses the blood-brain barrier with slower elimination than R-modafinil, enabling sustained brain exposure. Its mechanism involves elevating extracellular levels, which correlates with upregulated subtypes—particularly D1R in hippocampal CA1 and CA3 regions, and D5R in the —alongside increased total DAT expression, supporting and enhancement. Proteomic analyses further indicate influences on activity and reduced expression of proteins like S100B and α-synuclein, hinting at neuroprotective roles. As a candidate for cognitive therapeutics, CE-123 shows promise for conditions involving executive function impairments, though human trials remain pending.

Chemical Properties

Molecular Structure

CE-123 is a synthetic compound with the molecular formula C₁₇H₁₅NOS₂ for both the racemic mixture and its enantiomers. The active enantiomer, (S)-CE-123, shares this formula and has a molecular weight of 313.44 g/mol. The core structure of CE-123 features a 5-((benzhydrylsulfinyl)methyl)thiazole scaffold. This consists of a 1,3-thiazole ring—a five-membered heterocycle containing sulfur and nitrogen atoms—substituted at the 5-position with a -CH₂-S(O)-CH(Ph)₂ chain, where S(O) represents the sulfoxide group and CH(Ph)₂ is the diphenylmethyl (benzhydryl) moiety. In a 2D representation, the thiazole ring is depicted with the nitrogen at position 3 and sulfur at position 1, the methylene linker attached to carbon 5, followed by the chiral sulfur of the sulfoxide bonded to the central carbon of the diphenylmethyl group, which branches into two phenyl rings. CE-123 serves as a heterocyclic derivative of , which possesses a 2-[(diphenylmethyl)sulfinyl] structure. The key modification in CE-123 involves replacing modafinil's side chain (-CH₂-C(O)NH₂) with a ring, enhancing selectivity for the (DAT) while retaining the characteristic and diphenylmethyl elements. The group in CE-123 introduces a chiral center at the atom, resulting in (R) and (S) enantiomers. The (S)- exhibits greater pharmacological potency, particularly in DAT inhibition, compared to the (R)-, which contributes to its enhanced efficacy in cognitive enhancement models.

Synthesis and Preparation

The synthesis of CE-123, specifically the active (S)-, typically involves a four-step process starting from commercially available intermediates such as 5-(hydroxymethyl) and diphenylmethanol. The initial step entails the chlorination of 5-(hydroxymethyl) using in , yielding 5-(chloromethyl) hydrochloride in 95-100% yield on scales up to 500 g. Concurrently, diphenylmethanol reacts with in the presence of to form [(diphenylmethyl)sulfanyl]methanimideamide , achieving yields of 76-97% on scales from 1 g to 1 kg. These intermediates are then coupled under basic conditions with in to produce the thioether precursor, 5-((benzhydrylthio)methyl), in 76-95% yield on scales up to 1.3 kg. The key transformation to form the moiety occurs via enantioselective oxidation of the thioether precursor using a modified Kagan protocol, which employs (IV) isopropoxide, L-(+)-diethyl tartrate, diisopropylethylamine, and as the chiral oxidant system, followed by quenching with ferrous sulfate. This asymmetric sulfoxidation delivers (S)-CE-123 with >95% enantiomeric excess and 50-65% yield on scales from 1.3 g to 1.15 kg. For the racemic counterpart, oxidation can alternatively employ in glacial acetic acid, stirring for 12 hours to yield the sulfoxide in 59% isolated yield. Enantioselective preparation emphasizes the Kagan method's efficiency in achieving high optical purity without requiring post-synthesis resolution, though chiral or additional asymmetric oxidants have been explored in early characterizations to confirm >98% enantiomeric excess in purified samples. An alternative multi-step route for the core involves the Hantzsch thiazole synthesis from alpha-halo carbonyls and thioamides, followed by side-chain and oxidation, though commercial intermediates are preferred for scalability. Purification of (S)-CE-123 routinely includes using / (7:3) as eluent, followed by recrystallization from / mixtures and washing with aqueous and to enhance enantiomeric excess to >99% and chemical purity to >99%, suitable for preclinical research batches up to 1 kg. Extraction with and drying over precede final suspension in and vacuum filtration for racemic material. These processes ensure the compound's stability and homogeneity for pharmacological evaluation.

Pharmacology

Mechanism of Action

CE-123 functions primarily as a selective inhibitor of the (DAT), with its active (S)- demonstrating an EC50 of 2.76 μM in uptake inhibition assays using HEK293 cells stably expressing human DAT. This low-affinity binding profile is characteristic of atypical DAT inhibitors, enabling prolonged inhibition of despite modest potency, which distinguishes it from high-affinity classical stimulants like . The compound binds to DAT without serving as a substrate for transporter-mediated release, thereby avoiding amphetamine-like efflux of . The inhibition of DAT by (S)-CE-123 is non-competitive, primarily interacting with outward-facing conformations of the transporter to block substrate access, as evidenced by its atypical binding pattern compared to typical inhibitors. This mechanism elevates extracellular concentrations selectively in mesocorticolimbic pathways, including the and , without significant induction of vesicular release or locomotor stimulation. In microdialysis studies, systemic administration of (S)-CE-123 (10 mg/kg i.p.) increases dialysate levels in the infralimbic/prelimbic by approximately 150-200% above baseline within 40 minutes, reflecting enhanced tonic signaling in these regions. CE-123 exhibits high selectivity for DAT over other monoamine transporters, with negligible inhibition of the norepinephrine transporter (NET; IC50 > 82.8 μM, approximately 30-fold less potent) and (SERT; IC50 > 1.1 mM, >400-fold less potent), providing a more DAT-specific profile than (DAT IC50 ≈ 3.5 μM, NET IC50 ≈ 1.8 μM). Off-target effects on receptors such as the H3 are minimal, with no significant binding affinity reported in standard pharmacological screens. The resulting enhancement of signaling in the promotes downstream processes like through sustained activation of D1-like receptors, without the broad monoaminergic disruption seen in less selective agents. The kinetics of DAT inhibition by CE-123 can be modeled using a modified Michaelis-Menten equation for : v=Vmax⁡[S](Km+[S])(1+[I]Ki)v = \frac{V_{\max} [S]}{(K_m + [S]) (1 + \frac{[I]}{K_i})} where vv is the initial velocity of dopamine uptake, Vmax⁡V_{\max} is the maximum uptake rate, [S][S] is substrate () concentration, KmK_m is the Michaelis constant, [I][I] is inhibitor (CE-123) concentration, and KiK_i is the inhibition constant. This formulation accounts for the reduction in Vmax⁡V_{\max} without altering KmK_m, consistent with the non-competitive binding mode observed for atypical DAT inhibitors.

Pharmacokinetics

CE-123 demonstrates rapid absorption following intraperitoneal administration, with pharmacokinetic studies indicating penetration of the blood-brain barrier and attainment of effective concentrations within approximately 30 minutes in . In models, single daily doses have shown sustained efficacy, supporting once-daily dosing regimens in preclinical . The compound exhibits good distribution across biological compartments, particularly notable for its brain penetration. In Sprague-Dawley rats, the unbound brain-to-plasma partition coefficient (K_{p,uu,brain}) for the active (S)-enantiomer is 0.46, indicating efficient crossing of the blood-brain barrier and localization primarily in the brain interstitial space. Plasma protein binding is moderate, with an unbound fraction (f_u,plasma) of approximately 25% in rat plasma, determined via equilibrium dialysis. Higher concentrations are observed in dopamine-rich brain regions, consistent with its mechanism as a dopamine transporter inhibitor. Metabolism of CE-123 occurs primarily through hepatic oxidation, with the (S)- displaying stability and minimal . In human liver microsomes, S-CE-123 undergoes 9.3-fold faster metabolism compared to R-modafinil, with an of 39 minutes and intrinsic clearance of 3.6 μL/min/mg protein. Hydroxylated metabolites such as M1 (m/z 330.0624) have been identified in the oxidative pathway. Excretion is predominantly renal, though detailed clearance rates remain limited in available studies. In tissue distribution experiments following intravenous infusion (20 mg/kg), high partitioning into tissue was observed, suggesting renal elimination as a key route. The plasma half-life in supports the observed rapid clearance, contrasting with slower in vitro metabolic stability projections for s. Species differences highlight faster overall clearance in , with shorter in vivo exposure times compared to projected profiles based on microsome data. Preclinical pharmacokinetic parameters include a steady-state plasma concentration (C_{ss}) of approximately 4149 nM and unbound interstitial fluid concentration of 386 nM in rats. No Phase I data on AUC or C_{max} are publicly detailed as of 2023, but inform expectations of favorable exceeding 50%.

Medical Research

Cognitive Enhancement Studies

Preclinical studies in models have demonstrated that single doses of CE-123 (1-10 mg/kg, intraperitoneally) enhance memory performance in the radial arm maze task, with significant increases in indices observed during acquisition phases, particularly on training day 3. These effects were accompanied by elevated (DAT) and D1 receptor protein levels in hippocampal regions such as CA1 and CA3, supporting improved underlying . In attentional set-shifting tasks, CE-123 at low doses (0.3-1 mg/kg) improved by reducing the number of trials required for extra-dimensional shifts, with significant decreases in perseverative errors compared to vehicle controls (p < 0.001). This enhancement in executive function was attributed to CE-123's selective inhibition of DAT, promoting signaling in prefrontal circuits without inducing impulsive responding, unlike broader-acting stimulants. Compared to , CE-123 shows superior efficacy in tasks due to its higher DAT specificity, without the impulsivity deficits associated with . These findings highlight CE-123's potential as a targeted cognitive enhancer via selective modulation of mesocortical pathways. As of November 2025, all studies on CE-123 remain preclinical, with no human trials reported.

Other Therapeutic Investigations

Research into CE-123 has extended to neurodevelopmental disorders, particularly fetal alcohol spectrum disorders (FASD), where prenatal exposure leads to long-term behavioral and cognitive impairments in offspring. In models simulating FASD through neonatal ethanol administration (5 g/kg/day from postnatal days 4-9), CE-123 demonstrates therapeutic potential by mitigating ethanol-induced behavioral deficits. At doses of 3 and 10 mg/kg, acute administration significantly attenuates locomotor hyperactivity observed in young rats (postnatal day 21), reducing activity levels to those comparable to saline controls without altering baseline locomotion in non-exposed animals. Furthermore, CE-123 improves social in these FASD models, a key deficit linked to disrupted social interactions. Chronic treatment with 10 mg/kg (daily from postnatal days 10-20) prevents sex- and age-dependent impairments in social novelty discrimination, as measured by increased time spent exploring novel conspecifics in a three-chamber test; this effect is observed in both male rats at postnatal day 28 and female rats at postnatal day 42, accompanied by normalized hippocampal BDNF and TrkB expression levels. In addition, 10 mg/kg dosing ameliorates ethanol-induced deficits in reversal learning during (postnatal day 50), enhancing performance in the task by facilitating adaptation to spatial rule changes, indicative of improved in decision-making contexts. Ethanol-related impairments in decision-making are addressed in FASD models, highlighting CE-123's role in restoring prefrontal signaling disrupted by developmental exposure.

Development and Regulation

Discovery and History

CE-123 was developed in the mid-2010s as part of a series of heterocyclic analogs designed to achieve higher selectivity for the (DAT) compared to , addressing limitations in affinity and potential side effects associated with broader interactions. Researchers at the Department of Pharmaceutical Chemistry, , led by Gert Lubec, synthesized CE-123 to explore its potential as a agent with enhanced cognitive benefits. The compound, chemically known as 5-((benzhydrylsulfinyl)methyl), emerged from structure-activity relationship studies replacing 's diphenylmethyl group with a ring to improve DAT inhibition potency. The first synthesis of racemic CE-123 was accomplished through a four-step process starting from diphenylmethanol and , yielding the compound with high purity, as detailed in initial pharmacological evaluations conducted around 2016–2017. This work was published in 2017, marking the inaugural report on CE-123's cognitive effects in rat models of attentional set-shifting, highlighting its promise for improving without increasing . separation was achieved shortly thereafter using chiral HPLC with a Chiralpak IA column, identifying the (S)- as more potent at DAT inhibition. A follow-up study in 2018 further demonstrated CE-123's efficacy in memory acquisition and retrieval tasks. In 2018, a European patent (EP3553053A1) was filed by Gert Lubec, assigning rights to , covering the (S)- of CE-123 for its motivation-improving and reference memory-enhancing properties in treating cognitive decline. Process development reported in 2024 enabled scale-up to kilogram batches for preclinical studies, building on pharmacokinetic profiling from 2023 to support its potential. This progression reflected ongoing efforts to refine modafinil-like compounds for targeted DAT modulation, driven by the need for safer alternatives in cognitive enhancement applications.

Clinical Trials and Safety

Phase I clinical trials for CE-123 have not been initiated as of November 15, 2025, with all available data limited to preclinical studies in animal models. No entries for CE-123 appear on , indicating no registered human studies for , , or in conditions such as cognitive enhancement. Ongoing or planned human studies remain absent from public registries, though preclinical research suggests potential for Phase II investigations in ADHD or age-related cognitive decline once initial is established in humans. The compound's development appears to be in early stages, with no announced timelines for advancement to clinical phases. The human safety profile of CE-123 is unknown due to the lack of clinical data, precluding assessments of adverse events, potential, or interactions such as with inhibitors. Preclinical observations cannot substitute for human evidence, and cardiovascular effects or other risks remain uncharacterized in volunteers. Regulatory status positions CE-123 as an investigational compound without an approved (IND) application in the or equivalent in the EU, and it is not authorized for any therapeutic use by the FDA or EMA as of November 2025. Further regulatory milestones are pending preclinical completion and submission.
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