Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity
| العنوان: | Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity |
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| المؤلفون: | Anthony R. Harris, Susan M. Lotarski, Michael Aaron Brodney, Michael Popiolek, Catherine A. Thorn, Stephen Jenkinson, Che Wah Lee, Jennifer E. Davoren, Stefanus J. Steyn, Lei Zhang, Terrence Peter Kenakin, Betty Pettersen, Sarah Grimwood, Damien Webb, Michelle R. Garnsey, Simeon Ramsey, John T. Lazzaro, Steven Victor O'neil, Lisa Nottebaum, Jean-Philippe Fortin, Jeremy R. Edgerton |
| المصدر: | Journal of Medicinal Chemistry. 60:6649-6663 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Agonist, Allosteric modulator, medicine.drug_class, Chemistry, Allosteric regulation, Muscarinic acetylcholine receptor M1, Pharmacology, 03 medical and health sciences, 030104 developmental biology, Drug Discovery, Convulsion, medicine, Molecular Medicine, Cholinergic, Structure–activity relationship, medicine.symptom, Receptor |
| الوصف: | Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings pr... |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::e16d6e6b4f8608876f69c7501545a8c8 https://doi.org/10.1021/acs.jmedchem.7b00597 |
| رقم الأكسشن: | edsair.doi...........e16d6e6b4f8608876f69c7501545a8c8 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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