Work

Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions

Year: 2024

Type: article

Abstract: Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique “hinge-flip” binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.3c00523