1. Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines
- Author
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Kristin K. Brown, Jack D. Leber, Sharad K. Verma, Shu-Yun Zhang, Hong Lin, Brian Donovan, Mei Li, Dirk A. Heerding, Elisabeth A. Minthorn, Louis V. LaFrance, Kimberly A. Robell, Barry S. Brown, Juan I. Luengo, Igor G. Safonov, Wenyong Wang, Dennis S. Yamashita, Michael D. Schaber, Dennis T. Takata, Dana S. Levy, Jason A. Kahana, Joseph W. Venslavsky, Jin Zeng, Rakesh Kumar, Ren Xie, Anthony E. Choudhry, and Zhihong Lai
- Subjects
ERG1 Potassium Channel ,Pyridines ,Clinical Biochemistry ,hERG ,Aminopyridines ,Pharmaceutical Science ,Biochemistry ,Glycogen Synthase Kinase 3 ,Mice ,Structure-Activity Relationship ,Dogs ,Cytochrome P-450 Enzyme System ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Phosphorylation ,Protein Kinase Inhibitors ,Molecular Biology ,GSK3B ,Glycogen Synthase Kinase 3 beta ,biology ,Chemistry ,Organic Chemistry ,Biological activity ,Haplorhini ,Xenograft Model Antitumor Assays ,Ether-A-Go-Go Potassium Channels ,Rats ,Enzyme inhibitor ,Pyrazines ,biology.protein ,Molecular Medicine ,Tau-protein kinase ,Proto-Oncogene Proteins c-akt - Abstract
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
- Published
- 2010
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