Development of indazole mineralocorticoid receptor antagonists and investigation into their selective late-stage functionalization
| Autor: | Jinchu Liu, Maarten Hoek, Qiang Tan, Andreas Verras, Don Gauthier, Tim Cernak, Kevin D. Dykstra, Anthony Ogawa, Yun-Fang Yang, Shane W. Krska, Robert J. DeVita, Dong-Ming Shen, Beata Zamlynny, Thomas Bateman, Ravi Kurukulasuriya, Yili Chen, Lisa DiMichelle, Kun Liu, Alejandro Crespo, Petr Vachal, Jeffrey Madwed, Kendall N. Houk |
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| Rok vydání: | 2019 |
| Předmět: |
Indazole
Indazoles Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Clinical Biochemistry Late stage Pharmaceutical Science Metabolic stability 01 natural sciences Biochemistry Borylation Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Mineralocorticoid receptor Drug Development Drug Discovery Molecular Medicine Surface modification Molecular Biology Mineralocorticoid Receptor Antagonists |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(14) |
| ISSN: | 1464-3405 |
| Popis: | The derivatization of pharmaceuticals is a core activity in the discovery and development of new medicines. Late-stage functionalization via modern C H functionalization chemistry has emerged as a powerful technique with which to diversify advanced pharmaceutical intermediates. We report herein a case study in late-stage functionalization towards the development of a new class of indazole-based mineralocorticoid receptor antagonists (MRA). An effort to modify the electronics of the core indazole heterocycle inspired the use of modern C H borylation chemistry. New reactivity patterns were revealed and studied computationally. Ultimately, a de novo synthesis delivered a key 6-fluoroindazole compound 26, a potent MRA with excellent metabolic stability. |
| Databáze: | OpenAIRE |
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