Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers
Abstract ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeuti...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-99177-0 |
| _version_ | 1818834031102394368 |
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| author | Adam J. Davenport Ioana Neagoe Nico Bräuer Markus Koch Andrea Rotgeri Jens Nagel Alexis Laux-Biehlmann Frederic Machet Anne-Marie Coelho Susan Boyce Nikisha Carty Mark J. Gemkow Stephen D. Hess Thomas M. Zollner Oliver M. Fischer |
| author_facet | Adam J. Davenport Ioana Neagoe Nico Bräuer Markus Koch Andrea Rotgeri Jens Nagel Alexis Laux-Biehlmann Frederic Machet Anne-Marie Coelho Susan Boyce Nikisha Carty Mark J. Gemkow Stephen D. Hess Thomas M. Zollner Oliver M. Fischer |
| author_sort | Adam J. Davenport |
| collection | DOAJ |
| description | Abstract ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers. |
| first_indexed | 2024-12-19T02:28:21Z |
| format | Article |
| id | doaj.art-db0e029d06d746b6aa334c9d4e1c736d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T02:28:21Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-db0e029d06d746b6aa334c9d4e1c736d2022-12-21T20:39:50ZengNature PortfolioScientific Reports2045-23222021-10-0111111310.1038/s41598-021-99177-0Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibersAdam J. Davenport0Ioana Neagoe1Nico Bräuer2Markus Koch3Andrea Rotgeri4Jens Nagel5Alexis Laux-Biehlmann6Frederic Machet7Anne-Marie Coelho8Susan Boyce9Nikisha Carty10Mark J. Gemkow11Stephen D. Hess12Thomas M. Zollner13Oliver M. Fischer14Discovery Chemistry, Dorothy Crowfoot Hodgkin Campus, Evotec UKIn Vitro Pharmacology, Manfred Eigen Campus, Evotec SEPharmaceuticals Division, Drug Discovery, Candidate Generation & Exploration, Medicinal Chemistry, Bayer AGPharmaceuticals Division, Research and Development, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AGPharmaceuticals Division, Drug Discovery, Early Development, Drug Metabolism and Pharmacokinetics, Bayer AGPharmaceuticals Division, Research and Development, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AGResearch & Development, Pulmonary Drug Discovery Laboratory, Bayer US LLCIn Vivo Pharmacology, Campus Curie, Evotec SASIn Vivo Pharmacology, Manfred Eigen Campus, Evotec SEIn Vivo Pharmacology, Manfred Eigen Campus, Evotec SEIn Vitro Pharmacology, Manfred Eigen Campus, Evotec SENeurosciences, Manfred Eigen Campus, Evotec SEIn Vitro Pharmacology, Manfred Eigen Campus, Evotec SEPharmaceuticals Division, Research and Development, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AGPharmaceuticals Division, Research and Development, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AGAbstract ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.https://doi.org/10.1038/s41598-021-99177-0 |
| spellingShingle | Adam J. Davenport Ioana Neagoe Nico Bräuer Markus Koch Andrea Rotgeri Jens Nagel Alexis Laux-Biehlmann Frederic Machet Anne-Marie Coelho Susan Boyce Nikisha Carty Mark J. Gemkow Stephen D. Hess Thomas M. Zollner Oliver M. Fischer Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers Scientific Reports |
| title | Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| title_full | Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| title_fullStr | Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| title_full_unstemmed | Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| title_short | Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| title_sort | eliapixant is a selective p2x3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers |
| url | https://doi.org/10.1038/s41598-021-99177-0 |
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