1467057-27-7Relevant articles and documents
Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
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.
, p. 2372 - 2383 (2018/03/26)
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.
INDOLE AND INDAZOLE COMPOUNDS THAT ACTIVATE AMPK
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Paragraph 0711; 0714, (2013/10/22)
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.
