Delving into the Latest Updates on MK-1903 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NIACR1

Mechanism

NIACR1 agonists(Hydroxycarboxylic acid receptor 2 agonists)

Therapeutic Areas

Endocrinology and Metabolic DiseaseSkin and Musculoskeletal DiseasesCardiovascular Diseases

Active Indication-

Inactive Indication

AtherosclerosisDyslipidemiasLipid Metabolism Disorders+ [1]

Originator Organization

Arena Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Merck Sharp & Dohme LLC

Merck Sharp & Dohme Corp.Merck GmbH

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC8H8N2O2

InChIKeyCUTZNERBKDMLAP-QWWZWVQMSA-N

CAS Registry1268882-43-4

Introduction: Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia. Data: Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment ( r = .625, P < .019, Spearman’s test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (−.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets). Discussion: Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.

01 May 2023·Neuropharmacology

Potential role of the hydroxyl carboxylic acid receptor type 2 (HCAR2) in microglia pathophysiology: A possible cross-talk with C-X-C chemokine receptor 1 (CXCR1)

Review

Author: Maione, Sabatino ; Pagano, Martina ; Trotta, Maria Consiglia ; Parente, Andrea ; Guida, Francesca ; Ricciardi, Flavia ; Pieretti, Gorizio ; Infantino, Rosmara ; Perrone, Michela ; Luongo, Livio ; Fusco, Antimo ; Ricciardi, Federica ; Boccella, Serena ; Gargano, Francesca ; Giacca, Rosa ; Belardo, Carmela

Following insults or injury, microglia cells are activated contributing to the cytotoxic response or by promoting an immune-mediated damage resolution. Microglia cells express HCA2R, a hydroxy carboxylic acid (HCA) receptor, which has been shown to mediate neuroprotective and anti-inflammatory effects. In this study we found that HCAR2 expression levels were increased in cultured rat microglia cells after Lipopolysaccharide (LPS) exposure. In a similar fashion, the treatment with MK 1903, a potent full agonist of HCAR2, increased the receptor protein levels. Moreover, HCAR2 stimulation prevented i) cells viability ii) morphological activation iii) pro/anti-inflammatory mediators production in LPS-treated cells. Likewise, HCAR2 stimulation reduced the proinflammatory mediators mRNA expression induced by neuronal chemokine fractalkine (FKN), a neuronal derived chemokine activating its unique receptor, chemokine receptor 1 (CX3CR1) on microglia surface. Interestingly, electrophysiological recordings in vivo revealed that MK1903 was able to prevent the increase of the nociceptive neurons (NS) firing activity mediated by the spinal FKN application in healthy rats. Collectively, our data demonstrate that HCAR2 is functionally expressed in microglia, by showing its capability to shift microglia toward an anti-inflammatory phenotype. Moreover, we indicated the contribute of HCAR2 in the FKN signaling and suggested a possible HCAR2/CX3CR1 functional interaction. This study paves the way for further investigations aimed at understanding the role HCAR2 as potential target in neuroinflammation-based CNS disorders. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

01 Apr 2022·Glia

Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL‐18 and glutamatergic synaptic activity

Article

Author: Kong, Lingwei ; Weng, Han‐Rong ; Viatchenko‐Karpinski, Viacheslav

AbstractMany patients with systemic lupus erythematosus (SLE) live with chronic pain despite advances in medical management in reducing mortality related to SLE. Few animal studies have addressed mechanisms and treatment for chronic pain caused by SLE. In this study, we provide the first evidence for the analgesic effects of a GPR109A specific agonist (MK1903) and its action mechanisms in thermal hyperalgesia in female MRL/lpr mice, an SLE mouse model. Specifically, we show that MRL/lpr mice had a higher sensitivity to thermal stimuli at age 11–16 weeks, which was accompanied with significantly microglial and astrocytic activation, increases in p38 MAPK and glutamatergic synaptic activities in the spinal dorsal horn. We demonstrate that thermal hyperalgesia in MRL/lpr mice was significantly attenuated by intrathecal injection of MK1903. GPR109A was expressed in spinal microglia but not astrocytes or neurons. Its expression was significantly increased in MRL/lpr mice with thermal hyperalgesia. Activation of GPR109A receptors in microglia attenuated glutamatergic synaptic activity via suppressing production of interleukin‐18 (IL‐18). We provide evidence that activation of GPR109A attenuated thermal hyperalgesia in the SLE animal model via suppressing p38 MAPK activity and production of IL‐18. Our study suggests that targeting the microglial GPR109A is a potent approach for reversing spinal neuroinflammation, abnormal excitatory synaptic activity, and management of thermal hyperalgesia caused by SLE.

100 Deals associated with MK-1903

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Dyslipidemias	Phase 2	-	Merck Sharp & Dohme LLC	01 Jun 2008
Atherosclerosis	Phase 2	US	Merck GmbH	-
Atherosclerosis	Phase 2	-	Arena Pharmaceuticals, Inc.	-
Atherosclerosis	Phase 2	-	Merck Sharp & Dohme Corp.	-
Lipid Metabolism Disorders	Phase 2	US	Merck GmbH	-
Lipodystrophy	Phase 2	-	Arena Pharmaceuticals, Inc.	-
Lipodystrophy	Phase 2	-	Merck Sharp & Dohme Corp.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00847197 (1903-004, CTgov)	Phase 2	Dyslipidemias	191	placebo+MK1903 (MK1903)	timdyuzehs(smjttwosjd) = ouxfyuvywx qapzjafqie (pgxncxqwpi, ytarxgbwlu - qacpxryfxa) View more	-	22 Sep 2010
				placebo+MK1903 (Placebo)	timdyuzehs(smjttwosjd) = nyrrjamwgi qapzjafqie (pgxncxqwpi, zuhrbgalak - kpovtgueqc) View more