Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects

McColm, Juliet; Brittain, Clare; Suriyapperuma, Subha; Swanson, Steven; Tauscher-Wisniewski, Sitra; Foster, Joanne; Soon, Danny; Jackson, Kimberley

doi:10.1111/bcp.13252

Cited by 11 publications

(9 citation statements)

References 20 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These characteristics, such as the limited penetration into the CNS and the slow elimination from the CNS, likely arise from the hydrophilic property of MGS0008. A similar pharmacokinetic profile was also reported in a study examining LY2812223 in humans, the chemical structure of which resembles that of MGS0008 …”

Section: Discussionsupporting

confidence: 80%

“…A similar pharmacokinetic profile was also reported in a study examining LY2812223 in humans, the chemical structure of which resembles that of MGS0008. 24 The bioavailability after the oral administration of MGS0008 in monkeys was only 3.8%, whereas it was 78.1% in rats. Since MGS0008 was not metabolized in the preclinical species, the large species differences in oral bioavailability might be due to differences in the rates of its gastrointestinal absorption, such as transporter-mediated uptake in rats.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

Kinoshita

Ochi

Iwata

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

MGS0274 besylate is an ester‐based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half‐life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20‐fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

Kinoshita

Ochi

Iwata

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…Eli Lilly and Company discovered LY2812223 (Fig. 6), a mGluR2 agonist [136,137]. LY2812223 was found active in an animal model of psychosis, sensitive to mGluR2 [95,137].…”

Section: Metabotropic Glutamate 2 Receptor Agonist: Ly2812223mentioning

confidence: 99%

“…6), a mGluR2 agonist [136,137]. LY2812223 was found active in an animal model of psychosis, sensitive to mGluR2 [95,137]. Unfortunately, in the pharmacokinetic studies, LY2812223 showed a poor oral bioavailability (~ 4%).…”

Section: Metabotropic Glutamate 2 Receptor Agonist: Ly2812223mentioning

confidence: 99%

“…This randomized, placebocontrolled, phase II clinical trial will assess the efficacy (measured as the change from baseline in the NPI-Psychosis subscale score), safety, and pharmacokinetic profile of MP-101 (20-60 mg/day for 10 weeks), compared to placebo. LY2979165 was previously evaluated in healthy subjects, in whom it was overall well tolerated and showed a linear pharmacokinetic profile [53,137].…”

Section: Metabotropic Glutamate 2 Receptor Agonist: Ly2812223mentioning

confidence: 99%

See 1 more Smart Citation

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

et al. 2020

View full text Add to dashboard Cite

Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/ aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.

show abstract

Discovery of Subtype Selective Agonists of the Group II Metabotropic Glutamate Receptors

Hao

2022

Contemporary Accounts in Drug Discovery and Development

View full text Add to dashboard Cite

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects

Abstract: Oral doses of LY2979165 up to 60 mg as a single dose and up to 400 mg given as multiple QD doses, using a titration regimen, were well tolerated with linear PK. Overall, these data support further clinical evaluation of LY2979165.

Cited by 11 publications

References 20 publications

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

Discovery of Subtype Selective Agonists of the Group II Metabotropic Glutamate Receptors

Contact Info

Product

Resources

About