Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Surapaneni, Sekhar; Yerramilli, Usha; Bai, April; Dalvie, Deepak; Brooks, Jennifer L.; Wang, Xiaomin; Selkirk, Julie V.; Yan, Yingzhuo; Zhang, Peijin; Hargreaves, Richard; Kumar, Gondi; Palmisano, Maria; Tran, Jonathan Q.

doi:10.1124/dmd.120.000220

Cited by 55 publications

(41 citation statements)

References 19 publications

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“…This suggests that ST-2191 does not depend on Sphk2 for its immunomodulatory activity, but it does not rule out whether other active metabolites can be formed in vivo. Notably, the dual S1P 1+5 modulator ozanimod, which is currently in clinical trials for multiple sclerosis, inflammatory bowel disease and COVID-19, is metabolized to two active structures, which produce most of the clinical effects of the drug [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…Thus far, polymorphisms of Sphk2 have only been described for its promoter region, which affect the expression of the enzyme [ 32 ]. Overall, current S1PR modulators have disparate metabolisms, and while some become active without any modifications, others become active after phosphorylation by Sphk2 (fingolimod, mocravimod, amiselimod [ 24 , 25 ]), or a series of reactions by various enzymes to produce active metabolites such as ozanimod [ 26 ]. This highlights the need to dissect the in vivo metabolites that are produced following ST-2191 administration.…”

Section: Discussionmentioning

confidence: 99%

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ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

et al. 2021

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Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

et al. 2021

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“…Rate-limiting steps in the formation of the three metabolites were mediated via CYP and a combination of alcohol dehydrogenase/aldehyde dehydrogenase (ADH/ALDH) enzymes. However, a subsequent human mass balance/ADME study with 14 Cozanimod (1 mg) revealed a more complex picture (Surapaneni et al, 2021). Ozanimod was extensively metabolized via de novo metabolic pathways catalyzed by multiple non-CYP enzymes, including MAO B, carbonyl reductases (CBR), aldo-keto reductase (AKR), βhydroxysteroid dehydrogenases (β-HSD) (Figure 3) (Bai et al, 2021;Surapaneni et al, 2021).…”

Section: Drug Developmentmentioning

confidence: 99%

“…Moreover, ozanimod also underwent reductive metabolism in the gut microflora, which led to cleavage of its oxadiazole ring and the eventual formation of the corresponding benzoic acid metabolite (RP101124) (Surapaneni et al, 2021).…”

Section: Drug Developmentmentioning

confidence: 99%

Future of Biotransformation Science in the Pharmaceutical Industry

Kramlinger¹,

Dalvie²,

Heck³

et al. 2021

Drug Metab Dispos

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hydroxysteroid dehydrogenase; ISSX, international society for the study of xenobiotics; LC-MS/MS, liquid chromatography tandem mass spectrometry; MAO, monoamine oxidase; MIST, metabolites in safety testing; NIH, national institutes of health 4-OH-CTA, 4hydroxycrotonaldehyde; PK/PD, pharmacokinetics/pharmacodynamics; PROTAC, proteolysis targeting chimera; SAR, structure-activity relationship; t 1/2 , half-life.

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“…If the area under the plasma concentration-time curve (AUC) of disproportionate metabolites accounts for more than 10% of total drug-related exposure and the exposure levels to disproportionate metabolites in humans are not covered by levels in test species, additional safety assessment is required. Several recent studies have reported disproportionate metabolites (Sharma et al, 2014;Schadt et al, 2018;Zheng et al, 2018;Surapaneni et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective Na_V1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate

et al. 2021

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Predicting human disproportionate metabolites is difficult, especially when drugs undergo species-specific metabolism mediated by cytochrome P450s (P450s) and/or non-P450 enzymes. This study assessed human metabolites of DS-1971a, a potent Na v 1.7-selective blocker, by performing human mass balance studies and characterizing DS-1971a metabolites, in accordance with the Metabolites in Safety Testing (MIST) guidance. In addition, we investigated the mechanism by which the major human disproportionate metabolite (M1) was formed. After oral administration of radiolabeled DS-1971a, the major metabolites in human plasma were P450-mediated monoxidized metabolites M1 and M2 with area under the curve ratios of 27% and 10% of total drug-related exposure, respectively; the minor metabolites were dioxidized metabolites produced by aldehyde oxidase and P450s. By comparing exposure levels of M1 and M2 between humans and safety assessment animals, M1 but not M2 was found to be a human disproportionate metabolite, requiring further characterization under the MIST guidance. Incubation studies with human liver microsomes indicated that CYP2C8 was responsible for the formation of M1. Docking simulation indicated that, in the formation of M1 and M2, there would be hydrogen bonding and/or electrostatic interactions between the pyrimidine and sulfonamide moieties of DS-1971a and amino acid residues Ser100, Ile102, Ile106, Thr107, and Asn217 in CYP2C8, and that the cyclohexane ring of DS-1971a would be located near the heme iron of CYP2C8. These results clearly indicate that M1 is the predominant metabolite in humans and a human disproportionate metabolite due to species-specific differences in metabolism.

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Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Cited by 55 publications

References 19 publications

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

Future of Biotransformation Science in the Pharmaceutical Industry

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective Na_V1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate

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Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Cited by 55 publications

References 19 publications

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

Future of Biotransformation Science in the Pharmaceutical Industry

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate

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CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective Na_V1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate