2. Academic Validation
  3. Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors

Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors

  • ACS Med Chem Lett. 2020 Nov 19;11(12):2461-2469. doi: 10.1021/acsmedchemlett.0c00441.
Joey L Methot 1,  Abdelghani Achab 1,  Matthew Christopher 1,  Hua Zhou 1,  Meredeth A McGowan 1,  B Wesley Trotter 1,  Xavier Fradera 1,  Charles A Lesburg 1,  Peter Goldenblatt 1,  Armetta Hill 1,  Dapeng Chen 1,  Karin M Otte 1,  Martin Augustin 2,  Sanjiv Shah 1,  Jason D Katz 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 2 Proteros Biostructures, Martinsried 82152, Germany.
PMID: 33335668 DOI: 10.1021/acsmedchemlett.0c00441
Abstract

The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142646
    PI3K Inhibitor