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Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines |
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| Authors: | Hong Lin Dennis S Yamashita Ren Xie Jin Zeng Wenyong Wang Jack Leber Igor G Safonov Sharad Verma Mei Li Louis LaFrance Joseph Venslavsky Dennis Takata Juan I Luengo Jason A Kahana Shuyun Zhang Kimberly A Robell Dana Levy Rakesh Kumar Anthony E Choudhry Michael Schaber Dirk A Heerding |
| Institution: | 1. Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States;2. Oncology Biology, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States;3. Oncology Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States;4. Molecular Discovery Research, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States |
| 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 GSK3β and tumor growth in a BT474 tumor xenograft model in mice. |
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