2. Academic Validation
  3. Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions

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

  • ACS Med Chem Lett. 2024 Mar 7;15(4):486-492. doi: 10.1021/acsmedchemlett.3c00523.
Stefan McCarver 1,  Luke Hanna 1,  Andrew Samant 1,  Aaron A Thompson 1,  Mark Seierstad 1,  Arjun Saha 1,  Dongpei Wu 1,  Brian Lord 1,  Steven W Sutton 1,  Vishal Shah 1,  Cynthia M Milligan 1,  Michelle Wennerholm 1,  Jonathan Shelton 1,  Terry P Lebold 1,  Brock T Shireman 1
Affiliations

Affiliation

  • 1 Janssen Research and Development, San Diego, California 92121-1126, United States.
PMID: 38628796 DOI: 10.1021/acsmedchemlett.3c00523
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.

Figures
Products