Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors

  • Bioorg Med Chem Lett. 2020 Jan 1;30(1):126715. doi: 10.1016/j.bmcl.2019.126715.
Hua Zhou  1 ,  Meredeth A McGowan  2 ,  Kathryn Lipford  3 ,  Matthew Christopher  3 ,  Xavier Fradera  4 ,  David Witter  3 ,  Charles A Lesburg  4 ,  Chaomin Li  5 ,  Joey L Methot  3 ,  John Lampe  3 ,  Abdelghani Achab  3 ,  Lynsey Shaffer  6 ,  Peter Goldenblatt  6 ,  Sanjiv Shah  6 ,  Alan Bass  7 ,  Gottfried Schroeder  6 ,  Dapeng Chen  8 ,  Haoyu Zeng  9 ,  Martin A Augustin  10 ,  Jason D Katz  3
Affiliations
  • 1. Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].
  • 2. Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].
  • 3. Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 4. Department of Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 5. Department of Process Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 6. Department of In Vitro Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 7. Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 8. Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 9. Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 10. Proteros Biostructures GmbH, Bunsenstraße 7A, D-82152 Martinsreid, Germany.
PMID: 31757666 DOI: 10.1016/j.bmcl.2019.126715
Abstract

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Keywords
PI3Kδ inhibitor; Parallel medicinal chemistry; Phosphoinositide 3-kinase δ; Physicochemical properties; Structure-activity relationship.