Discovery of\n6‑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,\nPARP1-Selective Inhibitor

PARP inhibitors have attracted considerable\ninterest\nin drug discovery\ndue to the clinical success of first-generation agents such as olaparib,\nniraparib, rucaparib, and talazoparib. Their success lies in their\nability to trap PARP to DNA; however, first-generation PARP inhibitors\nwere not strictly optimized for trapping nor for selectivity among\nthe PARP enzyme family. Previously we described the discovery of the\nsecond-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.\nAZD5305 maintained the antitumor efficacy of first-generation PARP\ninhibitors while exhibiting lower hematological toxicity. Recently,\nthere has been interest in central nervous system (CNS)-penetrant\nPARP inhibitors for CNS malignancies and other neurological conditions;\nhowever, AZD5305 is not CNS penetrant. Herein we describe the discovery\nand optimization of a series of CNS-penetrant, PARP1-selective inhibitors\nand PARP1-DNA trappers, culminating in the discovery of AZD9574, a\ncompound that maintains the PARP1 selectivity of AZD5305 with improved\npermeability, reduced efflux, and increased CNS penetration.