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

Hua Zhou; Meredeth A McGowan; Kathryn Lipford; Matthew Christopher; Xavier Fradera; David Witter; Charles A Lesburg; Chaomin Li; Joey L Methot; John Lampe; Abdelghani Achab; Lynsey Shaffer; Peter Goldenblatt; Sanjiv Shah; Alan Bass; Gottfried Schroeder; Dapeng Chen; Haoyu Zeng; Martin A Augustin; Jason D Katz

doi:10.1016/j.bmcl.2019.126715

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. Epub 2019 Oct 18.

Authors

Hua Zhou¹, Meredeth A McGowan², Kathryn Lipford³, Matthew Christopher³, Xavier Fradera⁴, David Witter³, Charles A Lesburg⁴, Chaomin Li⁵, Joey L Methot³, John Lampe³, Abdelghani Achab³, Lynsey Shaffer⁶, Peter Goldenblatt⁶, Sanjiv Shah⁶, Alan Bass⁷, Gottfried Schroeder⁶, Dapeng Chen⁸, Haoyu Zeng⁹, Martin A Augustin¹⁰, Jason D Katz³

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.

MeSH terms

Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
High-Throughput Screening Assays / methods*
Humans
Piperazines / pharmacology
Piperazines / therapeutic use*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Structure-Activity Relationship

Substances

Piperazines
Protein Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases