- 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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- Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
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Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.
- Edmonds, David J.,Kung, Daniel W.,Kalgutkar, Amit S.,Filipski, Kevin J.,Ebner, David C.,Cabral, Shawn,Smith, Aaron C.,Aspnes, Gary E.,Bhattacharya, Samit K.,Borzilleri, Kris A.,Brown, Janice A.,Calabrese, Matthew F.,Caspers, Nicole L.,Cokorinos, Emily C.,Conn, Edward L.,Dowling, Matthew S.,Eng, Heather,Feng, Bo,Fernando, Dilinie P.,Genung, Nathan E.,Herr, Michael,Kurumbail, Ravi G.,Lavergne, Sophie Y.,Lee, Esther C.-Y.,Li, Qifang,Mathialagan, Sumathy,Miller, Russell A.,Panteleev, Jane,Polivkova, Jana,Rajamohan, Francis,Reyes, Allan R.,Salatto, Christopher T.,Shavnya, Andre,Thuma, Benjamin A.,Tu, Meihua,Ward, Jessica,Withka, Jane M.,Xiao, Jun,Cameron, Kimberly O.
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p. 2372 - 2383
(2018/03/26)
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- INDOLE AND INDAZOLE COMPOUNDS THAT ACTIVATE AMPK
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The present invention relates to indole and indazole compounds of Formula (I) that activate 5′ adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.
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Paragraph 0812
(2013/10/22)
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