Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

Autor:	Johannes JW; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Balazs AYS; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Barratt D; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Bista M; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Chuba MD; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Cosulich S; Oncology Projects, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Critchlow SE; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Degorce SL; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Di Fruscia P; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Edmondson SD; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Embrey KJ; New Modalities & Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 2NA, U.K., Fawell S; Oncology Discovery, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Ghosh A; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Gill SJ; Safety Sciences, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Gunnarsson A; Discovery Sciences, R&D Gothenburg, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Hande SM; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Heightman TD; Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Hemsley P; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Illuzzi G; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Lane J; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Larner CJB; Safety Sciences, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Leo E; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Liu L; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Madin A; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., McWilliams L; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., O'Connor MJ; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Orme JP; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Pachl F; Discovery Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Packer MJ; Computational Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Pei X; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Pike A; DMPK, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Schimpl M; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., She H; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Staniszewska AD; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Talbot V; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Underwood E; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Varnes JG; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Xue L; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Yao T; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Zhang K; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Zhang AX; Discovery Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Zheng X; Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 10. Date of Electronic Publication: 2024 Dec 10.
DOI:	10.1021/acs.jmedchem.4c01725
Abstrakt:	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.
Databáze:	MEDLINE
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