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Bioorg Med Chem Lett. 2020 Jan 1;30(1):126715. doi: 10.1016/j.bmcl.2019.126715. Epub 2019 Oct 18.

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

Author information

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.

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

PMID:
31757666
DOI:
10.1016/j.bmcl.2019.126715

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