2. Academic Validation
  3. Phosphoinositide-3-kinase inhibitors: evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511

Phosphoinositide-3-kinase inhibitors: evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511

  • Bioorg Med Chem Lett. 2014 Dec 15;24(24):5630-5634. doi: 10.1016/j.bmcl.2014.10.085.
Brian A Lanman 1,  Anthony B Reed 2,  Victor J Cee 2,  Fang-Tsao Hong 2,  Liping H Pettus 2,  Ryan P Wurz 2,  Kristin L Andrews 3,  Jian Jiang 4,  John D McCarter 5,  Erin L Mullady 6,  Tisha San Miguel 5,  Raju Subramanian 4,  Ling Wang 7,  Douglas A Whittington 8,  Tian Wu 9,  Leeanne Zalameda 5,  Nancy Zhang 7,  Andrew S Tasker 2,  Paul E Hughes 7,  Mark H Norman 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: blanman@amgen.com.
  • 2 Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 3 Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 4 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 5 Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 6 Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 7 Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 8 Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 9 Department of Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
PMID: 25466188 DOI: 10.1016/j.bmcl.2014.10.085
Abstract

Replacement of the piperazine sulfonamide portion of the PI3Kα Inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.

Keywords

Kinase inhibitor; Ligand efficiency; Phosphoinositide-3-kinase-alpha; Protein kinase B; Ribose pocket.

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