1467059-87-5Relevant articles and documents
Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577
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
, p. 681 - 696 (2018/05/23)
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.
INDOLE AND AZAINDOLE DERIVATIVE HAVING AMPK-ACTIVATING ACTIVITY
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Paragraph 0785-0788, (2015/07/27)
Disclosed is a compound which is useful as an AMPK activator. A compound represented by formula: or its pharmaceutically acceptable salt, wherein Y is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;T is —CR7═ or —N═;U is —CR8═ or —N═;R2 is hydrogen, halogen, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted alkyloxycarbonyl;R3 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or the like; andR4, R7 and R8 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or the like.
