Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis
| العنوان: | Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis |
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| المؤلفون: | Klaus Weigand, Andrea Vaupel, Roland Feifel, Berndt Oberhauser, Janet Dawson King, Mark Nash, Pius Loetscher, Amanda Littlewood-Evans, David Orain, Wolfgang Miltz, Juraj Velcicky |
| المصدر: | Journal of Medicinal Chemistry. 60:3672-3683 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Nociception, 0301 basic medicine, Angiogenesis, hERG, Administration, Oral, Neovascularization, Physiologic, Inflammation, Pharmacology, 01 natural sciences, Receptors, G-Protein-Coupled, Rats, Sprague-Dawley, Neovascularization, 03 medical and health sciences, Drug Discovery, medicine, Animals, Humans, Receptors, Histamine H3, Receptor, biology, 010405 organic chemistry, Chemistry, Antagonist, Rats, 0104 chemical sciences, HEK293 Cells, 030104 developmental biology, Drug Design, Hyperalgesia, biology.protein, Molecular Medicine, Female, medicine.symptom |
| الوصف: | A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01703 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d140d7ef0960f3398069f19f6c5bc89f https://doi.org/10.1021/acs.jmedchem.6b01703 |
| رقم الانضمام: | edsair.doi.dedup.....d140d7ef0960f3398069f19f6c5bc89f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.6b01703 |