Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure–Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1 Receptor Inverse Agonist
| العنوان: | Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure–Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1 Receptor Inverse Agonist |
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| المؤلفون: | Dennis Hyek, Jinshan Chen, R. Scott Obach, Melissa Wagenaar, Mark W. Bundesmann, Asser Bassyouni, Jeremy T. Starr, Maria S. Brown, Stephen Jenkinson, Manjinder S. Lall, Gregory Ciszewski, James Bradow, Gregory S. Walker, Senliang Pan, Douglas K. Spracklin, Bo Liu, Neal W. Sach, Daniel J Smaltz, Anne E. Hagen, Usa Reilly |
| المصدر: | Journal of Medicinal Chemistry. 63:7268-7292 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0303 health sciences, Chemistry, Nuclear magnetic resonance spectroscopy, Histamine H1 receptor, Loratadine, Histamine H1 Antagonists, Tandem mass spectrometry, 01 natural sciences, Combinatorial chemistry, Chemical space, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Drug Discovery, medicine, Molecular Medicine, Structure–activity relationship, Inverse agonist, 030304 developmental biology, medicine.drug |
| الوصف: | An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00483 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::4a4f2cd830cd5ca3994e400969ad8fd2 https://doi.org/10.1021/acs.jmedchem.0c00483 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi...........4a4f2cd830cd5ca3994e400969ad8fd2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.0c00483 |