Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-<i>N</i>-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor
PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.
Authors
- Giuditta Illuzzi (ORCID: https://orcid.org/0000-0003-1358-8424)
- Andrew X. Zhang (ORCID: https://orcid.org/0000-0003-0406-2404)
- Michał Biśta (ORCID: https://orcid.org/0000-0001-9237-1199)
- Andy Pike (ORCID: https://orcid.org/0000-0001-6078-7501)
- Paolo Di Fruscia (ORCID: https://orcid.org/0000-0002-2914-0651)
- Paul Hemsley
- Avipsa Ghosh (ORCID: https://orcid.org/0000-0003-3786-0453)
- Elisabetta Leo (ORCID: https://orcid.org/0000-0002-9761-8637)
- Andrew Madin
- Jeffrey Varnes
- Sébastien L. Degorce (ORCID: https://orcid.org/0000-0002-9478-5106)
- Anna D. Staniszewska (ORCID: https://orcid.org/0000-0003-1328-1959)
- Sonja J. Gill (ORCID: https://orcid.org/0000-0002-7273-9053)
- Sabina Cosulich (ORCID: https://orcid.org/0000-0001-9666-0510)
- Tom D. Heightman (ORCID: https://orcid.org/0000-0002-9109-4748)
- Verity Talbot
- Marianne Schimpl (ORCID: https://orcid.org/0000-0003-2284-5250)
- Carrie Larner (ORCID: https://orcid.org/0000-0002-4471-9135)
- Hongyao She
- Kevin J. Embrey
- Jeffrey W. Johannes (ORCID: https://orcid.org/0000-0001-7242-6682)
- Anders Gunnarsson (ORCID: https://orcid.org/0000-0002-6334-9520)
- Amber Balazs (ORCID: https://orcid.org/0000-0002-5556-6795)
- Tieguang Yao
- Scott D. Edmondson (ORCID: https://orcid.org/0000-0003-4865-2561)
- Fiona Pachl
- Xiaohui Pei
- Susan E. Critchlow (ORCID: https://orcid.org/0000-0002-4647-8988)
- Martin J. Packer (ORCID: https://orcid.org/0000-0002-2457-2703)
- Mark J. O’Connor (ORCID: https://orcid.org/0000-0003-1823-625X)
- Lisa McWilliams (ORCID: https://orcid.org/0000-0002-0613-8647)
- Jonathan P. Orme
- Jordan Lane (ORCID: https://orcid.org/0000-0002-0853-7457)
- Matthew D. Chuba
- Stephen E. Fawell (ORCID: https://orcid.org/0000-0002-1962-891X)
- Lina Liu (ORCID: https://orcid.org/0000-0001-6957-0114)
- Ke Zhang (ORCID: https://orcid.org/0000-0002-4562-5405)
- Xiaolan Zheng
- Elizabeth Underwood
- Lin Xue
- Derek Barratt
- Sudhir M. Hande
Institutions
- AstraZeneca (United Kingdom) (GB)
- Bioscience Research (US)
- AstraZeneca (South Korea) (KR)
- Translational Research in Oncology (FR)
- AstraZeneca (Brazil) (BR)
- Pharmaceutical Product Development (India) (IN)
- AstraZeneca (Poland) (PL)
- Computational Physics (United States) (US)
- Drug Safety Research Unit (GB)
- AstraZeneca (Sweden) (SE)
- Molecular Oncology (United States) (US)
- AstraZeneca (United States) (US)
- The Deputy Prime Minister's Office (GB)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-10
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01725
- Citations
- 23
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 6.50