Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

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 SchaberZhihong Lai, Barry S. Brown, Brian T. Donovan, Elisabeth A. Minthorn, Kristin K. Brown, Dirk A. Heerding

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)684-688
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number2
DOIs
StatePublished - Jan 15 2010
Externally publishedYes

Keywords

  • AKT kinase inhibitors
  • Aminopyridines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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