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
  • 1. Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: [email protected].
  • 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.