Discovery of an Orally Bioavailable and Brain Penetrant Selective Estrogen Receptor Degrader

Despite that many oral SERDs have been reported in the literature, most of them do not have adequate CNS penetration. Here, we report our efforts in discovering brain penetrant oral SERDs to address the unmet medical need for Breast Cancer patients with brain metastasis (BCBM). Our strategy to convert the acrylic acid-containing motif of ZN-c5 to a basic amine-containing tail resulted in compounds with much improved brain penetration and excellent ER degradation activity. Further optimization led to the discovery of compound 5 with excellent in vitro and in vivo efficacy. Compound 5 showed good in vitro ADME properties, good oral bioavailability in mouse, rat, and dog, as well as superior brain penetration, which translated into excellent efficacy in multiple brain metastasis breast Cancer mouse models.