2. Academic Validation
  3. Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors

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

Affiliations

  • 1 Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: hua_zhou2@merck.com.
  • 2 Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: meredeth.mcgowan@merck.com.
  • 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.

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