Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease

Article

Author: Zhang, Ruijia ; Ye, Haoyu ; Yang, Letian ; Duan, Huaichuan ; Ma, Liang ; Peng, Jing ; Ye, Neng ; Chen, Lijuan ; Hu, Jianping ; Su, Kaiyue ; Zhang, Xinlu ; Tang, Minghai ; Cai, Xiaoying ; Li, Na ; Wu, Wenshuang ; Zhao, Min ; Qiu, Qiang ; Jiang, Xueqin ; Tang, Lingkai ; Tang, Lei

Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13a with the respective IC₅₀ of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 μg·h/L. Oral administration of 13a (0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.

02 Sep 2024·ChemMedChem

An Investigation on Linker Modifications of Cyanoguanidine‐Based P2X7 Receptor Antagonists

Article

Author: Kassiou, Michael ; Larik, Fayaz Ali ; McKenzie, Andre D. J. ; Danon, Jonathan J. ; Gilchrist, Jayson ; Garrett, Taylor R. ; Werry, Eryn L.

AbstractDespite their acknowledged significance in the inflammatory signalling cascade across a range of disease states, P2X7R antagonists have not yet proven to be effective in clinical trials. In this study, we present findings on P2X7 receptor antagonists that are based on a core adamantyl‐cyanoguanidine‐quinoline lead. To investigate the specific features of the cyanoguanidine moiety that influence compound potency we carried out a structure‐activity relationship (SAR) study. Compound potency was assessed using an in vitro dye‐uptake assay measuring P2X7R pore formation. While none of the compounds displayed superior potency to the lead, we established key structural requirements for potent P2X7R antagonism. An additional SAR using different aryl groups was performed based on the promising activity displayed by the squaramide derivative.

02 Apr 2024·Expert Opinion on Therapeutic Patents

A patent review of P2X7 receptor antagonists to treat inflammatory diseases (2018–present)

Review

Author: Bano, Sehrish ; Huang, Qing ; Iqbal, Jamshed ; Khan, Imtiaz Ali

INTRODUCTIONThe purinergic P2X7 receptor (P2X7R) is expressed on the surface of many different types of cells, including immune cells. Targeting P2X7R with antagonists has been studied for its potential therapeutic effects in a variety of inflammatory illnesses.AREA COVEREDMany chemical substances, including carboxamides, benzamides and nitrogen containing heterocyclic derivatives have demonstrated promising inhibitory potential for P2X7 receptor. The chemistry and clinical applications of P2X7R antagonists patented from 2018- present are discussed in this review.EXPERT OPINIONPurinergic receptor inhibitor discovery and application has demonstrated the potential for therapeutic intervention, as demonstrated by pharmacological research. Few chemical modalities have been authorized for use in clinical settings, despite the fact that breakthroughs in crystallography and chemical biology have increased the knowledge of purinergic signaling and its consequences in disease. The many research projects and pharmaceutical movements that sustain dynamic P2X receptor programs over decades are evidence of the therapeutic values and academic persistence in purinergic study. P2X7R is an intriguing therapeutic target and possible biomarker for inflammation. Although several companies like Merck and AstraZeneca have published patents on P2X3 antagonists, the search for P2X7R antagonists has not stopped. Numerous pharmaceutical companies have disclosed different scaffolds, and some molecules are presently being studied in clinical studies.

News (Medical) associated with P2X7 receptor antagonists(Chengdu University)

25 Jul 2023

·www.pharmaceutical-technology.com

Golgi and Breye partner to develop P2X7 receptor antagonist programme

Diabetic retinopathy is one of the main reasons for blindness among working-age adults. Credit: Alexander Grey from Pixabay. Golgi Neurosciences has joined forces with Breye Therapeutics for the development of a P2X7 receptor antagonist programme. The receptor, a vital inflammation switch, is an adenosine triphosphate (ATP) gated ion channel found in several cell types. Recommended Reports Reports Beta 2 Adrenergic Receptor (Beta 2 Adrenoreceptor or ADRB2) Drugs in Development by Therapy Areas... GlobalData Reports D2 Dopamine Receptor (Dopamine D2 Receptor or DRD2) Drugs in Development by Therapy Areas and Ind... GlobalData View all Companies Intelligence Breye Therapeutics ApS View all The oral P2X7 receptor antagonists offer a new treatment approach for both early-stage diabetic retinopathy (DR) and dry age-related macular degeneration (dry AMD). Golgi Neurosciences managing director Chiara Liberati said: “With leading experts on the Scientific Advisory Board, Breye is led by a strong and seasoned Management team, supported by a highly-regarded syndicate of investors, making Breye the ideal partner to facilitate the next steps in advancing our P2X7 receptor antagonist program towards developing innovative approaches for retinal disorders.” DR impacts around 30% of individuals with diabetes and is one of the main reasons for blindness among working-age adults. AMD is a significant factor contributing to the loss of vision, especially among individuals aged 60 years and older. Breye Therapeutics CEO Ulrik Mouritzen said: “The Golgi incubator has fantastic expertise in neurosciences, and we are pleased to collaborate to advance the P2X7 receptor antagonist programme for retinal disorders, where there is a large unmet medical need for more effective and less burdensome therapies.” Based in Milan, Italy, Golgi is involved in the discovery and development of small molecule-based therapies for neurodegenerative diseases. Breye is focused on the development of novel, oral ophthalmology drugs for DR and AMD.

100 Deals associated with P2X7 receptor antagonists(Chengdu University)

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Kidney Diseases	Preclinical	China	Chengdu University	23 Sep 2024

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