2. Academic Validation
  3. Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT

Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT

  • Bioorg Med Chem Lett. 2018 Jun 1;28(10):1887-1891. doi: 10.1016/j.bmcl.2018.03.092.
Saravanan Parthasarathy 1,  Kenneth Henry 2,  Huaxing Pei 2,  Josh Clayton 2,  Mark Rempala 2,  Deidre Johns 2,  Oscar De Frutos 3,  Pablo Garcia 3,  Carlos Mateos 3,  Sehila Pleite 3,  Yong Wang 2,  Stephanie Stout 2,  Bradley Condon 4,  Sheela Ashok 4,  Zhohai Lu 2,  William Ehlhardt 2,  Tom Raub 2,  Mei Lai 2,  Sandaruwan Geeganage 2,  Timothy P Burkholder 2
Affiliations

Affiliations

  • 1 Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285-0150, United States. Electronic address: shakthisarav@gmail.com.
  • 2 Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285-0150, United States.
  • 3 Lilly S.A., Avda.de la Industria 30, 28108 Alcobendas, Madrid, Spain.
  • 4 Lilly Research Laboratories, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, United States.
PMID: 29655979 DOI: 10.1016/j.bmcl.2018.03.092
Abstract

During the course of our research efforts to develop potent and selective Akt inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/Akt with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective Akt inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.

Keywords

AKT inhibitor; ATP competitive; GSK3β; Orally bioavailable.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112148
    Akt Inhibitor
    Akt