Delving into the Latest Updates on MK-1903 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

MK 1903, MK1903

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-

Structure

Molecular FormulaC8H8N2O2

InChIKeyCUTZNERBKDMLAP-QWWZWVQMSA-N

CAS Registry1268882-43-4

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

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 ; Viatchenko‐Karpinski, Viacheslav ; Weng, Han‐Rong

Abstract:

Many 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.

01 Dec 2014·AtherosclerosisQ2 · MEDICINE

Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity

Q2 · MEDICINE

Article

Author: Toma, Jelena ; Chan, Pak ; Robson, Debra L ; Hughes-Large, Jennifer M ; Borradaile, Nica M ; Pang, Dominic K T

OBJECTIVE:

Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD(+), niacin could elicit these vascular benefits through NAD(+)-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved.

METHODS AND RESULTS:

Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD(+) precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD(+) and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin.

CONCLUSION:

Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD(+) biosynthesis and SIRT1 activation, but rather through niacin receptor activation.

100 Deals associated with MK-1903

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Dyslipidemias	Phase 2	-	Merck Sharp & Dohme LLC	01 Jun 2008
Dyslipidemias	Phase 2	-	Merck Sharp & Dohme Corp.	01 Jun 2008
Lipid Metabolism Disorders	Phase 2	US	Merck GmbH	-
Lipodystrophy	Phase 2	-	Merck Sharp & Dohme Corp.	-
Lipodystrophy	Phase 2	-	Arena Pharmaceuticals, Inc.	-
Atherosclerosis	Phase 1	US	Merck GmbH	-
Atherosclerosis	Phase 1	-	Arena Pharmaceuticals, Inc.	-
Atherosclerosis	Phase 1	-	Merck Sharp & Dohme Corp.	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00847197 (1903-004, CTgov)	Phase 2	Dyslipidemias	191	placebo+MK1903 (MK1903)	zkxykzjswm(ilbnpkjchz) = ditugukflx vxwrovcsul (zxymceblrc, hwjztraacw - xqymqcsujx) View more	-	22 Sep 2010
				placebo+MK1903 (Placebo)	zkxykzjswm(ilbnpkjchz) = bbbupwskcv vxwrovcsul (zxymceblrc, atpnvuabyt - ktspocelik) View more