The small molecular CCR3 antagonist YM344031 attenuates neurodegenerative pathologies and improves learning and memory performance in a mouse model of Alzheimer’s disease

Q4 · MEDICINE

Article

Author: Sun, Xiaohong ; Xu, Bing ; Zhang, Yao ; Sui, Yi ; Dong, Chunyao

The chemokine C-C receptor 3 (CCR3) plays a role in the pathogenesis of Alzheimer's disease (AD). Based on our previous observations that deletion of CCR3 prevented neurodegenerative pathologies in amyloid precursor protein/presenilin 1 (APP/PS1) double-transgenic mice, we hypothesize that CCR3 antagonists may provide therapeutic benefits to AD. To this end, we examined the effect of the brain-penetrable CCR3 antagonist, YM344031, on AD-related pathologies in APP/PS1 double transgenic mice. Treatment of 10-month-old APP/PS1 double-transgenic mice with YM344031 (50 mg/kg, b.i.d.) for two months resulted in dramatic decreases in β-amyloid deposition, tau hyperphosphorylation and synaptic loss in the forebrain, significant attenuation of microgliosis and astrogliosis, and marked improvement of spatial learning and memory performance compared with the vehicle-treated mice. These results support CCR3 antagonism as a potential therapeutic strategy for AD.

28 Feb 2013·Investigative Opthalmology & Visual ScienceQ2 · MEDICINE

Suppression of Laser-Induced Choroidal Neovascularization by a CCR3 Antagonist

Q2 · MEDICINE

ArticleOA

Author: Nozaki, Miho ; Tokoro, Mayumi ; Ogura, Yuichiro ; Mizutani, Takeshi ; Ashikari, Masayuki

PURPOSETo evaluate the efficacy of a novel CCR3 antagonist for laser injury-induced choroidal neovascularization (CNV) in mice.METHODSWe evaluated YM-344031, a novel and selective small-molecule CCR3 antagonist. CNV was induced by laser injury in C57BL/6J mice, and its volume was measured after 7 days by confocal microscopy. Leakage from the CNV was also measured after 7 days by fluorescein angiography. The CCR3 antagonist was administered by gavage at 1 hour before and 1 day after the laser injury, or intravitreous injection immediately after the laser injury. After the laser injury, ELISA, Western blot analysis, and real-time RT-PCR for VEGF-A expression in the RPE/choroid, and immunohistochemistry for CCR3, CCL11, Ki67, and Rac1 was performed.RESULTSBoth oral administration and intravitreous injection of YM-344031 significantly suppressed the CNV volume (P < 0.0001 and P < 0.01, respectively). Pathologically significant leakage was significantly less common in YM-344031-injected mice (P < 0.0001). The mean VEGF protein level was significantly increased in vehicle-injected eyes after the laser injury (P < 0.05). Although the YM-344031-injected eyes did not show VEGF-A suppression after the laser injury, VEGF164 mRNA upregulation was significantly suppressed in YM-344031-injected mice (P < 0.05), and intravitreous injection of YM-344031 appeared to suppress CCR3, CCL11 (eotaxin), Ki67, and Rac1 expression after the laser injury.CONCLUSIONSThe present data suggest that the CCR3 antagonist YM-344031 can suppress CNV, via suppression of the upregulation of VEGF164 mRNA in VEGF isoform after the laser injury. Although our findings may warrant further investigation, YM-344031 may have potential as a new therapy for age-related macular degeneration.

01 Jan 2006·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031

Q3 · BIOLOGY

Article

Author: Tatsuaki Morokata ; Koichiro Takahashi ; Masayuki Kaneko ; Yasuaki Shimizu ; Ippei Sato ; Koichiro Morihira ; Satoko Takizawa ; Keiko Suzuki

Eosinophils play a prominent proinflammatory role in a broad range of diseases, including atopic dermatitis and asthma. Eotaxin-1 and its receptor CCR3 are implicated in the recruitment of eosinophils from blood into inflammatory tissues, therefore inhibition of Eotaxin-1/CCR3 interaction may have therapeutic potential for allergic inflammation with eosinophil infiltration. YM-344031, a novel and selective small molecule CCR3 antagonist, potently inhibited ligand binding (IC(50)=3.0nM), ligand-induced Ca(2+) flux (IC(50)=5.4nM), and the chemotaxis of human CCR3-expressing cells (IC(50)=19.9nM). YM-344031 (1-10mg/kg) orally administered to cynomolgus monkeys significantly inhibited Eotaxin-1-induced eosinophil shape change in whole blood. Additionally, orally administered YM-344031 (100mg/kg) prevented both immediate- and late-phase allergic skin reactions in a mouse allergy model. YM-344031 therefore has potential as a novel and orally available compound for the treatment of allergic inflammation, such as atopic dermatitis and asthma.

100 Deals associated with YM-344031

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Discovery	-	Yamanouchi Pharmaceutical Co., Ltd.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

YM-344031

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation