From dopamine 4 to sigma 1: synthesis, SAR and biological characterization of a piperidine scaffold of s1 modulators

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer’s disease (AD) and other neurodegenerative disorders. In addition, modulators of s1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D4 and s1 activity. In addition, we further profile lead compounds in panel of off-target receptors, in vitro and in vivo pharmacokinetic studies. This has culminated in the discovery of multiple s1 receptor modulators with properties that will allow for study in animal models.