Discovery of Potent, Orally Bioavailable, and CNS-Penetrant 1,2,3-Triazolopyridinyl Piperazine-Based PARP1-Selective Inhibitors

Abstract Hematological toxicities have resulted in limiting the dose of first-generation PARP inhibitors, which have activity at both PARP1 and PARP2. With the advancement of selective PARP1 inhibitors to the clinic, we embarked on a program to identify novel PARP1 inhibitors that are suitable for the treatment of CNS malignancies. Central to our design was the replacement of the carboxamide in saruparib with a series of heterocycles. Our progression criteria included using Caco-2 efflux instead of the more commonly used MDR1-MDCK efflux to enable identifying compounds with Kpu,u >0.3. This work culminated in the discovery of the potent, selective, orally bioavailable, and CNS-penetrant PARP1 inhibitor 33, which demonstrated tumor growth inhibition and regression in xenograft models at 0.2 mg/kg QD. Predicted human PK parameters coupled with a tumor growth PKPD model for 33 estimated an efficacious clinical dose of <150 mg once daily.