Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions

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Poly(ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics with enhanced selectivity and cytotoxicity in BRCA1/2 mutant cancer cells. AZD2461, a congener of FDA approved olaparib, is a potent PARPi with high affinity for PARP-1 and nonsubstrate for P-glycoprotein (P-gp), an attractive characteristic for cancer therapeutics. Analogues of AZD2461 were synthesized and profiled in BRCA1 functional and nonfunctional cell lines, revealing compounds (2, 3, and 5) of low cytotoxicity and excellent PARP-1 affinities (∼4–8 nM). In comparison to AZD2461, these agents were found to be less stimulating of P-gp, suggesting that these compounds may be excellent candidates for neurological applications where blood brain barrier penetrance is sought.