Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577
| Autor: | Daniel W. Widlicka, Nathan E. Genung, Jana Polivkova, Daniel W. Kung, Wiglesworth Kristin, Thomas Andrew Brandt, Jun Xiao, Matthew S. Dowling, Yingxin Zhang, Paul M. Herrinton, David J. Edmonds, Todd Zahn, Ka Ning Yip, Colin R. Rose, Qifang Li, Jane Panteleev, Shawn Cabral, Andre Shavnya, Nandell F. Keene, John D. Weaver, Benjamin A. Thuma, Michael Herr, Ian Edmonds, Gary Erik Aspnes, Guoqiang Wang, Philip D. Dent, Dilinie P. Fernando, Aaron C. Smith, Michael G. Vetelino, Sophie Y. Lavergne, Edward L. Conn |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Organic Process Research & Development. 22:681-696 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.8b00059 |
| Popis: | Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of 1 and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified. |
| Databáze: | OpenAIRE |
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