2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles |
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| Authors: | Hong Lin Dennis S Yamashita Jin Zeng Ren Xie Sharad Verma Juan I Luengo Nelson Rhodes Shuyun Zhang Kimberly A Robell Anthony E Choudhry Zhihong Lai Rakesh Kumar Elisabeth A Minthorn Kristin K Brown Dirk A Heerding |
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| 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 |
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| Abstract: | A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3β phosphorylation in a BT474 tumor xenograft model in mice. |
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