In Vitro and in Vivo Evaluation of the Metabolism and Bioavailability of Ester Prodrugs of Mgs0039 (3-(3,4-DICHLOROBENZYLOXY)-2-AMINO-6-FLUOROBICYCLO[3.1.0]HEXANE-2,6-DICARBOXYLIC Acid), a Potent Metabotropic Glutamate Receptor Antagonist

Nakamura, Masato; Kawakita, Yasunori; Yasuhara, Akira; Fukasawa, Yoshiki; Yoshida, Kōji; Sakagami, Kazunari; Nakazato, Atsuro

doi:10.1124/dmd.105.006213

Cited by 14 publications

(6 citation statements)

References 23 publications

(19 reference statements)

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“…37,38 Group II mGluR antagonists have drawn attention as potential therapeutic compounds for the treatment of depression, anxiety and cognitive disorders. Inhibition of Group II mGluR in rodents enhances working memory, spatial learning and social recognition, 10,39 while also exhibiting acute and chronic antidepressant-like/anxiolytic effects.…”

Section: Resultsmentioning

confidence: 99%

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse

et al. 2014

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Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.

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Section: Resultsmentioning

confidence: 99%

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse

et al. 2014

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“…The basis for this therapeutic prediction comes from the convergent biologic effects of LY3020371 and that of ketamine, an NMDA receptor antagonist that produces rapid and persistent relief of depression symptoms in treatmentresistant depression patients (Zarate et al, 2006;Abdallah et al, 2015). Prior studies have also suggested the efficacy of mGlu2/3 receptor antagonists in depression (Chaki et al, 2004;Witkin and Eiler, 2006;Witkin et al, 2016a), and two mGlu2/3 antagonists have entered clinical development: BCI-838 (Yasuhara et al, 2006;Nakamura et al, 2006), an oral prodrug of orthosteric antagonist BCI-632, also known as MGS0039 (Nakazato et al, 2004;Yoshimizu et al, 2006) and RO4995819, also known as RG1538 (Decoglurant), an mGlu2/3 negative allosteric modulator (Gatti et al, 2006;clinicaltrials.gov, study NCT01457677).…”

Section: Discussionmentioning

confidence: 99%

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Witkin

Mitchell

Wafford

et al. 2017

J Pharmacol Exp Ther

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The ability of the -methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1,2,3,4,5,6)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

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“…As carboxyl groups can undergo deprotonation, molecules bearing carboxyl groups are usually negatively charged under physiological conditions, which makes them difficult to penetrate the negatively charged cell membrane. Many marketed drugs use simple esterification to enhace oral bioavailability and absorption in the treatment of many severe diseases, such as enalapril (an angiotensin-converting enzyme inhibitor), oseltamivir (an anti-influenza drug) and MGS0210 (a glutamate receptor antagonist)212223.…”

mentioning

confidence: 99%

Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents

Wang

Chen

et al. 2016

Sci Rep

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Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2′-bipyridine-4,4′-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes.

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In Vitro and in Vivo Evaluation of the Metabolism and Bioavailability of Ester Prodrugs of Mgs0039 (3-(3,4-DICHLOROBENZYLOXY)-2-AMINO-6-FLUOROBICYCLO[3.1.0]HEXANE-2,6-DICARBOXYLIC Acid), a Potent Metabotropic Glutamate Receptor Antagonist

Cited by 14 publications

References 23 publications

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents

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