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Intepirdine

Intepirdine (also known as SB-742457 or RVT-101) is an investigational small-molecule drug that acts as a selective antagonist of the 5-hydroxytryptamine 6 (5-HT₆) receptor, with potential applications in enhancing cognition, memory, and learning in neurodegenerative conditions.^[1] Originally developed by GlaxoSmithKline (GSK), the compound was licensed to Axovant Sciences in December 2014 for $5 million plus royalties, after GSK discontinued its internal program.^[2] Axovant advanced intepirdine primarily as an adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease, targeting synaptic and cognitive deficits associated with the disorder.^[3] Clinical development of intepirdine included multiple Phase 2 trials exploring its effects on Alzheimer's, dementia, and Parkinson's disease, where some early data suggested potential benefits in functional aspects like daily activities at a 35 mg dose.^[4] However, the pivotal Phase 3 MINDSET trial, a randomized, double-blind, placebo-controlled study involving 1,315 patients on stable donepezil across 19 countries, failed to demonstrate statistically significant improvements in co-primary endpoints of cognition (measured by ADAS-Cog) or activities of daily living (measured by ADCS-ADL) after 24 weeks of 35 mg daily dosing. A subsequent Phase 2b trial in dementia with Lewy bodies (HEADWAY-DLB) also showed no benefit and was terminated, leading Axovant to abandon further development of intepirdine in January 2018 in favor of gene therapy programs. Despite its failures in late-stage trials, intepirdine highlighted ongoing interest in 5-HT₆ receptor modulation for Alzheimer's, a field where no new symptomatic treatments have been approved in over 15 years.^[7] The drug exhibited a safety profile comparable to placebo, with no major adverse events beyond those typical of the patient population.^[8] As of 2025, intepirdine remains unapproved and is not commercially available, though its chemical structure (C₁₉H₁₉N₃O₂S) continues to be studied in preclinical contexts for cognitive enhancement.^[9]

Medical research

Alzheimer's disease

Intepirdine, a selective 5-HT6 receptor antagonist, was investigated for Alzheimer's disease (AD) due to the role of 5-HT6 receptors in modulating neurotransmitter systems critical for cognition. These receptors are highly expressed in brain regions such as the hippocampus and frontal cortex, which are involved in memory and learning processes disrupted in AD. Preclinical studies demonstrated that 5-HT6 antagonism enhances acetylcholine, glutamate, and other neurotransmitter release, leading to improved cognitive performance in animal models of AD, providing a rationale for its potential as an adjunctive therapy to existing cholinesterase inhibitors like donepezil.^[10] Early clinical evaluation in Phase II trials supported this approach. In Study 866, a randomized, placebo-controlled trial involving 684 patients with mild-to-moderate AD on stable donepezil therapy, intepirdine at 35 mg/day showed statistically significant improvements over placebo at week 24 on the co-primary endpoints: the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P=0.012) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; P=0.033). These findings suggested potential benefits in cognition and functional abilities, prompting advancement to Phase III.^[11] The pivotal Phase III MINDSET trial, conducted from 2015 to 2017, evaluated intepirdine as adjunctive therapy in 1,315 patients with mild-to-moderate AD already on donepezil. Participants received 35 mg/day intepirdine or placebo for 24 weeks, with co-primary endpoints of change from baseline in ADAS-Cog and ADCS-ADL scores. The trial failed to meet these endpoints, showing no significant differences (ADAS-Cog: P=0.2249; ADCS-ADL: P=0.8260), and key secondary outcomes, including the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+; P=0.0234 showed nominal benefit but was not adjusted for multiplicity), Neuropsychiatric Inventory (NPI), and other cognitive measures, also lacked consistent benefits over placebo. No improvements were observed in behavioral symptoms or other secondary domains.^[11] The MINDSET results, announced in September 2017, underscored persistent challenges in AD drug development, such as patient heterogeneity, trial design complexities, and the difficulty in replicating Phase II efficacy in larger populations. Consequently, Axovant Sciences discontinued further development of intepirdine for AD, halting its pursuit as a treatment for cognitive and functional impairments in this indication.^[12]

Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is characterized by cognitive decline, parkinsonism, visual hallucinations, and fluctuating cognition, with no approved disease-modifying treatments available. Intepirdine, a selective 5-HT6 receptor antagonist, was investigated for its potential to address these symptoms through enhancement of cholinergic neurotransmission and modulation of motor function, building on preclinical and clinical evidence suggesting benefits for broader dementia-related impairments.^[13] The rationale stemmed from 5-HT6 receptor antagonism's role in increasing acetylcholine release, which could mitigate cholinergic deficits common in DLB, alongside observations of motor improvements in prior studies.^[13] The HEADWAY-DLB trial (NCT02669433), a phase IIb, multinational, randomized, double-blind, placebo-controlled study conducted from 2016 to 2018, evaluated intepirdine in 269 patients aged 50-85 with mild-to-moderate DLB (MMSE score 14-26).^[13] Participants, who were required to be on stable doses of cholinesterase inhibitors, were randomized 1:1:1 to receive placebo, 35 mg/day intepirdine, or 70 mg/day intepirdine for 24 weeks across 61 sites in seven countries.^[13] The primary endpoint was the change in motor function as measured by the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) from baseline to week 24, with co-secondary endpoints including cognition (ADAS-Cog11) and global function (Clinician's Interview-Based Impression of Change plus carer interview, CIBIC+).^[13] Tertiary endpoints encompassed additional cognitive, behavioral, and neuropsychiatric measures.^[13] The trial did not meet its primary endpoint, with the 35 mg dose showing a 2.01-point worsening on UPDRS-III compared to placebo (p=0.158) and the 70 mg dose a 0.74-point improvement (p=0.607).^[13] Similarly, no significant differences were observed in co-secondary endpoints: for ADAS-Cog, the 35 mg dose showed a 0.47-point worsening (p=0.653) and 70 mg a 0.67-point improvement (p=0.527) versus placebo; for CIBIC+, improvements were 0.15 points (p=0.395) and 0.07 points (p=0.701), respectively.^[13] Numerical trends favoring the 35 mg dose were noted in some secondary measures of cognition and function, though none reached statistical significance.^[14] Safety was consistent with prior studies, with higher rates of gastrointestinal adverse events in the intepirdine arms (16.3% for 35 mg, 21.2% for 70 mg vs. 11.5% placebo), but overall tolerability was good, with an 83.6% completion rate.^[13] Following the negative results from HEADWAY-DLB, along with failures in other indications, Axovant Sciences discontinued the intepirdine development program in January 2018.^[14] Prior to this trial, intepirdine had been evaluated in 21 completed clinical trials involving over 2,000 subjects, providing extensive data on dosing (favoring 35 mg for efficacy signals) and long-term safety that informed its application in DLB.^[13] Despite the lack of efficacy, HEADWAY-DLB represented one of the largest controlled studies in DLB to date, highlighting challenges in targeting motor and cognitive symptoms.^[13]

Parkinson's disease

Intepirdine was also explored in Parkinson's disease dementia (PDD) as part of a small pilot Phase 2 trial (NCT02910102) evaluating its effects on gait and balance in patients with dementia, including those with PDD, Alzheimer's disease, and DLB. Conducted in 2016-2017 with approximately 40 participants, the study tested 35 mg/day intepirdine over 12 weeks but showed no improvement in gait speed or balance compared to placebo. This negative result, announced in January 2018, contributed to the overall discontinuation of the intepirdine program.^[14]^[15]

Pharmacology

Mechanism of action

Intepirdine acts primarily as a selective antagonist at the 5-HT6 serotonin receptor (HTR6), demonstrating high binding affinity with a pKi of 9.6 (Ki ≈ 0.25 nM).^[16] This compound exhibits greater than 100-fold selectivity over other receptor subtypes, including no significant activity at additional serotonin receptors beyond a moderate affinity at 5-HT2A (pKi 8.0).^[16] Its pharmacological profile underscores a targeted blockade of 5-HT6 signaling without substantial interference from off-target interactions. The 5-HT6 receptor is a G(s)-protein-coupled receptor enriched in brain regions critical for cognition, such as the striatum, hippocampus, and olfactory tubercle.^[17] Activation of this receptor stimulates adenylyl cyclase, elevating intracellular cyclic AMP (cAMP) levels and influencing downstream effectors involved in neuronal excitability and synaptic function.^[18] Intepirdine antagonism interrupts this pathway, preventing serotonin-induced cAMP accumulation and thereby modulating associated signaling cascades.^[19] By blocking 5-HT6 receptors, intepirdine is proposed to enhance cholinergic and glutamatergic neurotransmission, key systems implicated in learning and memory.^[20] This occurs through disinhibition of presynaptic release mechanisms, where 5-HT6 activation normally suppresses acetylcholine and glutamate efflux; antagonism thus promotes their increased availability in cortical and hippocampal circuits.^[21] The resulting alterations in synaptic plasticity, including potentiated long-term potentiation, may contribute to cognitive benefits observed in preclinical models.^[22] Intepirdine shows minimal affinity for dopamine receptors (e.g., D1, D2) or adrenergic receptors (e.g., α1, β1), further supporting its clean selectivity profile.^[23]

Pharmacokinetics

Intepirdine is administered orally as a tablet and is rapidly absorbed, with peak plasma concentrations typically attained within 2-4 hours following dosing, though human oral bioavailability has not been fully characterized. Steady-state plasma concentrations are achieved within 7 days of daily administration at doses such as 35 mg, with an accumulation ratio consistent with its elimination kinetics.^[24] The drug is lipophilic (computed logP = 2.5), enabling it to cross the blood-brain barrier effectively, as evidenced by a brain-to-blood ratio of ~0.5:1 in preclinical rat models.^[25]^[26] Metabolism of intepirdine occurs primarily in the liver through cytochrome P450 enzymes, including CYP3A4 (for which it is also a moderate inhibitor) and CYP2D6, producing major inactive metabolites. The terminal elimination half-life is approximately 30 hours in humans. Excretion is predominantly fecal (>70% of the dose), with minimal renal clearance (<10%).^[24] Drug interactions may occur with strong CYP3A4 inhibitors (e.g., ketoconazole), which can increase intepirdine exposure by inhibiting its metabolism; conversely, no clinically significant pharmacokinetic interactions were observed with co-administration of donepezil or memantine in clinical studies. Intepirdine shows no notable effect on the pharmacokinetics of risperidone, though a modest increase in risperidone Cmax (15-19%) was noted.^[24]^[27]

Development history

Discovery and preclinical studies

Intepirdine, originally designated as SB-742457, was discovered by GlaxoSmithKline (GSK) in the early 2000s as part of a targeted medicinal chemistry program focused on developing selective 5-HT6 receptor antagonists for cognitive enhancement in neurological disorders. This effort built on high-throughput screening efforts initiated around 1998 to identify ligands for the 5-HT6 receptor, leading to the optimization of compounds like SB-742457 through structure-activity relationship studies aimed at improving potency and selectivity.^[28] Preclinical rationale for SB-742457 stemmed from evidence that 5-HT6 receptor antagonism could enhance cholinergic and glutamatergic neurotransmission, addressing cognitive deficits without disrupting normal function. In animal models, such as scopolamine-induced memory impairment in rats—a standard paradigm for anticholinergic cognitive disruption—SB-742457 improved cognition and memory performance via 5-HT6 blockade, while exhibiting no adverse effects on cognition in healthy animals. These findings positioned it as a candidate for Alzheimer's disease, where similar neurotransmitter imbalances occur.^[27] Key preclinical findings included dose-dependent reversal of cognitive deficits in validated rodent assays, notably the novel object recognition task, where SB-742457 restored discrimination indices impaired by scopolamine, and the Morris water maze, where it facilitated acquisition and retention of spatial memory. Safety assessments in rodents and dogs confirmed a favorable profile, supporting safe escalation to human studies with no observed genotoxicity in standard assays or cardiovascular liabilities at therapeutic exposures.^[29]^[27] GSK discontinued internal development of SB-742457 in 2014 following mixed Phase II results, prompting the licensing of worldwide rights to Roivant Neurosciences in December 2014, which formed Axovant Sciences to advance it. The agreement included a $5 million upfront payment, an additional $5 million upon specified development triggers, up to $70 million in regulatory milestones, up to $85 million in sales milestones, and 12.5% royalties on net sales. Axovant initiated Phase III trials in 2015, leveraging the compound's preclinical validation.^[30]

Clinical trials

Intepirdine (also known as SB-742457 or RVT-101) underwent an extensive clinical development program primarily sponsored by GlaxoSmithKline (GSK) until 2014, followed by Axovant Sciences, encompassing 21 trials involving over 2,000 subjects across Phases I through III for Alzheimer's disease and dementia with Lewy bodies (DLB).^[31]^[32] Phase I studies, completed by GSK in the 2000s, focused on safety and tolerability in healthy volunteers and established doses up to 35 mg demonstrating good tolerability, with primarily mild gastrointestinal side effects reported.^[32]^[31] These early trials, part of GSK's initial 13 studies involving over 1,250 participants, confirmed the drug's acceptable pharmacokinetic profile and supported advancement to patient populations.^[31] Phase II development included at least six completed trials, primarily in Alzheimer's disease and early explorations in DLB, enrolling more than 1,000 patients overall.^[33] Key examples featured randomized, placebo-controlled designs evaluating intepirdine as monotherapy or adjunctive therapy to donepezil. In a 24-week monotherapy trial (NCT00224497) with 576 patients with mild-to-moderate Alzheimer's, doses of 15 mg and 35 mg showed no significant cognitive benefits on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) compared to placebo, though donepezil (active comparator) demonstrated efficacy.^[27] A companion 48-week adjunctive trial (NCT00710684) with 684 patients on stable donepezil reported positive signals at 35 mg, including a 1.5-point improvement in ADAS-Cog (p=0.012 at week 24; p=0.024 at week 48) and a 1.9-point gain in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; p=0.033 at week 24), suggesting potential additive effects on cognition and function.^[27] Safety across these trials was favorable, with adverse events (e.g., nausea, diarrhea) occurring at rates similar to placebo (around 60% incidence), and no serious drug-related issues identified.^[27] Early DLB investigations, including a pilot gait and balance study (NCT02910102), provided preliminary data but did not advance standalone indications at this stage.^[34] Phase III trials, led by Axovant after acquiring rights from GSK in 2014, targeted mild-to-moderate Alzheimer's and DLB but ultimately failed to meet primary endpoints. The MINDSET trial (NCT02585934), a 24-week randomized, placebo-controlled study of 35 mg intepirdine adjunctive to donepezil in 1,315 patients with Alzheimer's, reported in 2017, showed no statistically significant improvements in cognition (ADAS-Cog) or daily activities (ADCS-ADL) versus placebo.^[8] The HEADWAY-DLB trial (NCT02669433), a 24-week Phase IIb/III study in 269 DLB patients at 35 mg and 70 mg doses, announced in 2018, demonstrated no primary benefit on Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) motor scores or cognition, leading to program termination.^[13]^[35] Common adverse events in these late-stage trials, such as nausea and diarrhea, remained comparable to placebo rates, with no new safety signals emerging.^[8]^[13] Following these failures, Axovant discontinued intepirdine development in January 2018, with no regulatory approval pursued and no ongoing studies as of 2025.^[36]^[32]

Chemistry

Structure and properties

Intepirdine has the molecular formula C₁₉H₁₉N₃O₂S and a molecular weight of 353.44 g/mol.^[9] Its IUPAC name is 3-(benzenesulfonyl)-8-piperazin-1-ylquinoline (CAS 607742-69-8), and it is classified as a selective antagonist of the serotonin 5-HT₆ receptor.^[37]^[38] The molecular structure of intepirdine features a quinoline core, a bicyclic aromatic heterocycle consisting of a fused benzene and pyridine ring. At the 3-position of the quinoline, a benzenesulfonyl group (-SO₂C₆H₅) is attached, providing the sulfonyl functionality. The 8-position of the quinoline bears a piperazin-1-yl substituent, a six-membered heterocyclic ring with two nitrogen atoms at positions 1 and 4, where the nitrogen at position 1 is directly bonded to the quinoline. This arrangement contributes to its pharmacological profile as a 5-HT₆ receptor ligand.^[37]^[39] Intepirdine is typically isolated as a white to beige powder. It has a melting point of 183–185 °C and exhibits moderate lipophilicity with a calculated logP (XLogP3) value of 2.83. The compound is insoluble in water but soluble in organic solvents such as DMSO (50–60 mg/mL) and ethanol (2 mg/mL). Other computed physicochemical properties include a topological polar surface area of 70.68 Å², one hydrogen bond donor, five hydrogen bond acceptors, and three rotatable bonds, all of which satisfy Lipinski's rule of five for potential oral bioavailability.^[9]^[38]^[37]^[40]^[41] Intepirdine is stable under standard laboratory conditions and recommended for storage at 2–8 °C, or -20 °C for long-term preservation. It presents no unusual hazards beyond typical irritant properties associated with fine powders.^[9]^[40]

Synthesis

Intepirdine, also known as SB-742457, is synthesized through a multi-step process that assembles the quinoline core with key substituents, including the phenylsulfonyl group at the 3-position and the piperazin-1-yl group at the 8-position. The route begins with 3-iodo-8-nitroquinoline as a key intermediate, which undergoes copper-mediated coupling with sodium phenylsulfinate and copper(I) triflate in N,N-dimethylformamide at 65°C to introduce the phenylsulfonyl moiety, yielding 8-nitro-3-(phenylsulfonyl)quinoline in 58% yield.^[42] Subsequent reduction of the nitro group using titanium(III) chloride in tetrahydrofuran and hydrochloric acid at temperatures below 35°C affords 8-amino-3-(phenylsulfonyl)quinoline in 72% yield. This amine is then diazotized with n-butyl nitrite in acetonitrile at low temperature (<5°C), followed by treatment with tetra(n-butyl)ammonium iodide to generate 8-iodo-3-(phenylsulfonyl)quinoline in 75% yield. The final substitution at the 8-position is achieved via a palladium-catalyzed Buchwald-Hartwig amination by coupling the iodo intermediate with 1-(tert-butoxycarbonyl)piperazine, using Pd₂(dba)₃ and sodium tert-butoxide in 1,4-dioxane at 40°C (76% yield), followed by deprotection with HCl in dioxane (68% yield) to afford the free base; the hydrochloride salt is formed by treatment with HCl in dioxane/ethanol.^[42] This synthetic sequence, detailed in GlaxoSmithKline patents, focuses on the efficient installation of the pharmacophoric elements while maintaining high selectivity for the 5-HT₆ receptor. The process is designed for laboratory-scale production and has been adapted for clinical supply, though specific GMP scalability details are proprietary. The route licensed to Axovant Sciences follows this GSK-developed pathway without major variants for the core structure.^[42]

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Intepirdine ; Formula Wt. 353.44 ; Chemical Name. 3-(Phenylsulfonyl)-8-(1-piperazinyl)quinoline ; IUPAC Name. 3-(benzenesulfonyl)-8-piperazin-1-ylquinoline.Missing: structure properties<|control11|><|separator|>
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Compound Properties. Melting Point (0). 183-185 °C. Source(s). Other Names and Identifiers. InChI. InChI=1S/C19H19N3O2S/c23-25(24,16-6-2-1-3-7-16)17-13-15-5-4-8 ...Missing: solubility logP
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