Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate

Shram, Megan J.; Setnik, Beatrice; Webster, Lynn R.; Guenther, Sven; Mickle, Travis; Braeckman, René; Kański, Jarosław; Martin, Andrea E.; Kelsh, Debra; Vince, Bradley; Barrett, Andrew C.

doi:10.1080/03007995.2022.2076474

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…d-MPH has previously been used independently as a first-line ADHD treatment, as it increases dopamine and norepinephrine extracellularly and acts as an agonist at serotonin 5-HT1A receptors [48]. SDX/d-MPH has this same activity with decreased addictive properties when compared to d-MPH alone, though the combination drug is to be classified as a Class-IV controlled substance [49]. The prodrug, SDX, must be activated in the lower GI tract, suggesting a reduced risk of diversion in the body, less risk of alternative routes of administration, and overall reduced risk of abuse and substance misuse [49].…”

Section: In the Year 2021 Sdx/d-mph For Adhdmentioning

confidence: 99%

A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022)

Giliberto,

Shishodia,

Nastruz

et al. 2024

Cureus

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Mental health disorders are among the top leading causes of disease burden worldwide and many patients have high levels of treatment resistance. Even though medications offer improvement to some patients, antidepressants are only effective in about half of those treated, and schizophrenia is treatment-refractory in about one-third of patients. One way to combat this disparity is to improve medication development and discovery for psychiatric disorders through evidence-based research. Recently, most psychiatric medications approved by the United States Food and Drug Administration (FDA) are for increased tolerability or extended release. Because of the slow, incremental progress, there is a pressing need to explore novel medications with new indications or mechanisms of action to treat the expanding population with mental disorders, especially in those who are fully or partially recalcitrant to first-line medication options. This review aims to present the newest FDA medications with new indications, establish the clinical need for each, and discuss future directions in drug development. We searched and reviewed novel psychiatric medications approved by the FDA from 2018 to 2022. We then analyzed each medication in the United States Clinical Trials Registry and gathered updated results for efficacy and safety information. We also searched PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, Web of Science, Elsevier, and Google Scholar to understand how these new indications met current clinical needs. Finally, we inquired about related technological implications that will lead the field of psychopharmacology now and in the years to come. We found 12 novel psychiatric medications approved by the FDA from 2018 to 2022, representing a very small percentage of the total FDA approvals during that period. These psychiatric medications with novel mechanisms or improved efficacy and safety are expected to provide further options for treating mental health disorders; promising results will lead to new patterns of research.

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Section: In the Year 2021 Sdx/d-mph For Adhdmentioning

confidence: 99%

A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022)

Giliberto,

Shishodia,

Nastruz

et al. 2024

Cureus

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“…This medication consists of a prodrug/drug co-formulation of serdexmethylphenidate ( 7 ) and dexmethylphenidate (7.6) in a 70:30 molar ratio. Dexmethylphenidate 7.6 was previously approved as a monotherapy for ADHD and marketed as Focalin by Novartis in 2002 . The prodrug, serdexmethylphenidate ( 7 ), is comprised of the pharmacologically active dexmethylphenidate attached to a nicotinoyl- l -serine moiety via a carboxymethylene linker.…”

Section: Cns Drugsmentioning

confidence: 99%

“…Dexmethylphenidate 7.6 was previously approved as a monotherapy for ADHD and marketed as Focalin by Novartis in 2002. 70 The prodrug, serdexmethylphenidate (7), is comprised of the pharmacologically active dexmethylphenidate attached to a nicotinoyl-L-serine moiety via a carboxymethylene linker. Catabolism of serdexmethylphenidate ( 7) is believed to occur in the lower gastrointestinal tract.…”

Section: Serdexmethylphenidate and Dexmethylphenidate (Azstarys)mentioning

confidence: 99%

Synthetic Approaches to the New Drugs Approved During 2021

McInturff,

France,

Leverett

et al. 2023

J. Med. Chem.

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Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody−drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021. ■ SIGNIFICANCEThis publication presents a synopsis of the synthetic approaches to new drugs that were approved in 2021, based on the largest scale of synthesis that has been disclosed in primary literature and/or patents. This provides a view of the practical synthetic methods that are applicable to drug discovery and development and a holistic perspective on the molecular complexity of novel drug molecules and synthetic methods required to manufacture them.

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“…It consists of a single d-DMP molecule covalently attached via a carbamate bond to a methylene oxide linker, which in turn is connected to a nicotinoyl-serine moiety, as illustrated in Fig. 1B [4]. The chemical name of DMP is (R,R)-( +)-Methyl 2-phenyl-2-(2-piperidyl)acetate [1,2], {the d-( +) throe-enantiomer of methylphenidate} [1,2] and its structural formula is shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, co-formulation of SER.DMP with DMP allows for a more rapid onset of action while still retaining longer therapeutic efficacy [ 3 ]. In addition, SER.DMP has lower abuse potential than DMP [ 4 ]. Dexmethylphenidate (DMP) appears to block the reuptake of norepinephrine and dopamine into the presynaptic neuron, increasing their availability in the extracellular space.…”

Section: Introductionmentioning

confidence: 99%

Chromatographic reversed HPLC and TLC-densitometry methods for simultaneous determination of serdexmethylphenidate and dexmethylphenidate in presence of their degradation products—with computational assessment

et al. 2023

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Two Chromatographic methods have been established and optimized for simultaneous determination of serdexmethylphenidate (SER.DMP) and dexmethylphenidate (DMP) in the presence of their degradation products. The first method is a reversed phase high performance liquid chromatography with diode array detection (HPLC–DAD). Isocratic separation was carried out on Waters X-bridge Shield RP18 column (150×3.9×5 μm particle size) using a mixture of 5 mM phosphate buffer (pH 5.5): acetonitrile (40:60, v/v) as a mobile phase, flow rate 1 mL/min and detection at 220 nm. The second method is a thin-layer chromatography (TLC)—densitometry method using methanol: chloroform (70:30, v/v) as a mobile phase and UV scanning at 220 nm. In HPLC method, the linearity range of SER.DMP was (2.5–25 μg/mL); with LOD (0.051 μg/mL) and LOQ (0.165 μg/mL) while for DMP was (2.5–25 μg/mL); with LOD and LOQ of (0.098 μg/mL) and (0.186 μg/mL), respectively. For TLC method the sensitivity range of SER.DMP was (5–25 μg/mL), LOD was (0.184 μg/spot), while LOQ was (0.202 μg/ spot) whereas for DMP the sensitivity range was (5–25 μg/mL) with LOD of (0.115 μg/ spot) and LOQ of (0.237 μg/ spot), respectively. SER.DMP was found to be equally labile to acidic and alkaline hydrolysis, whereas DMP was sensitive to acidic hydrolysis only. Both drugs were successfully determined in presence of acidic and basic degradants by the two developed methods (stability indicating assay method). Chromatographic separation of the degradation products was carried out on TLC aluminum silica plates 60 F254, as a stationary phase, using methanol: dichloroethane: acetonitrile (60:20:20 v/v), as a mobile phase. The degradation pathway was confirmed using TLC, IR, 1H-NMR and mass spectroscopy; moreover, the separation power was correlated to the computational results by applying molecular dynamic simulation. The developed methods were validated according to the International Conference on Harmonization (ICH) guidelines demonstrating good accuracy and precision. They were successfully applied for quantitation of SER.DMP and DMP in pure and capsule forms. The results were statistically compared with those obtained by the reported method in terms of accuracy, precision and robustness, and no significant difference was found.

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Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate

Cited by 5 publications

References 32 publications

A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022)

A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022)

Synthetic Approaches to the New Drugs Approved During 2021

Chromatographic reversed HPLC and TLC-densitometry methods for simultaneous determination of serdexmethylphenidate and dexmethylphenidate in presence of their degradation products—with computational assessment

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