- PYRIDAZINE DERVATIVES FOR MODULATING NUCLEIC ACID SPLICING
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The present disclosure features compounds and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.
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Page/Page column 197; 218
(2021/09/04)
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- Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577
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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.
- Smith, Aaron C.,Kung, Daniel W.,Shavnya, Andre,Brandt, Thomas A.,Dent, Philip D.,Genung, Nathan E.,Cabral, Shawn,Panteleev, Jane,Herr, Michael,Yip, Ka Ning,Aspnes, Gary E.,Conn, Edward L.,Dowling, Matthew S.,Edmonds, David J.,Edmonds, Ian D.,Fernando, Dilinie P.,Herrinton, Paul M.,Keene, Nandell F.,Lavergne, Sophie Y.,Li, Qifang,Polivkova, Jana,Rose, Colin R.,Thuma, Benjamin A.,Vetelino, Michael G.,Wang, Guoqiang,Weaver, John D.,Widlicka, Daniel W.,Price Wiglesworth, Kristin E.,Xiao, Jun,Zahn, Todd,Zhang, Yingxin
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p. 681 - 696
(2018/05/23)
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- ANTAGONISTS OF PROSTAGLANDIN EP3 RECEPTOR
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Provided herein are antagonists la or lb of prostaglandin EP3 receptor, processes to make said antagonists, and methods comprising administering said antagonists to a mammal in need thereof. (Formula I)
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Page/Page column 48; 49
(2016/07/27)
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