 CK1 delta (CK1d) and CK1 epsilon (CK1e) are closely related members of a family of seven mammalian serine/threonine protein kinases previously known as casein kinases. The CK1d and CK1e isoforms are highly expressed in the suprachiasmatic nucleus (SCN) where they form an essential component of the mammalian biological clock. Selective inhibitors of this class of Kinases will provide tools to study the role of circadian clock in CNS disorders such as: morning lark, bipolar or unipolar depression. A challenge with targeting Kinase inhibitors for chronic CNS indications is a seemingly insurmountable task because of the need to achieve good brain penetration for efficacy and high selectivity for safety. Through a combination of structure-based design, computational chemistry, and innovative medicinal chemistry we have identified a series of highly selective, brain penetrant CK1d inhibitors which demonstrated phase shift in mouse and cynomolgus monkey models of circadian rhythm. These inhibitors also provided excellent therapeutic index in exploratory toxicology studies. This presentation will highlight the discovery of such compounds as well as general guidelines for targeting kinases for CNS disorders.

Succeeding in an unprecedented CNS target space: Discovery of selective casein kinase (CK1d/e) inhibitors for the treatment of circadian rhythm disorder

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.