Substituted cyclopentanes, tetrahydrofurans and pyrrolidines as orexin-1-receptor antagonists for treatment of various CNS disorders (WO2015/055994; WO2015/124932; WO2015/124934)

ABSTRACT

The three patent applications WO2015/055994, WO2015/124932 and WO2015/124934 from Takeda Pharmaceuticals describe antagonists for the orexin-1 receptor, based on saturated substituted five-membered carbo- or heterocycles. According to the patent applications, the compounds have utility in therapeutic areas such as schizophrenia and other psychotic disorders, anxiety or addiction disorders, among others. The patent applications together describe almost 300 examples, and for most of them activity data, determined by Fluorescence Imaging Plate Reader (FLIPR) technology on the orexin-1 as well as the orexin-2 receptor, are disclosed. Structurally, the building blocks used to prepare the compounds are reminiscent of other orexin antagonist programs recently disclosed in the literature. However, the templates used are novel in the orexin antagonist field and are probably the key feature for the selectivity of the derivatives towards the orexin-1 receptor.

KEYWORDS:

• Orexin-1-selective antagonists (1SORAs)
• anxiety
• addiction
• schizophrenia
• G-protein coupled receptors (GPCR)
• Takeda Pharmaceutical Co

Declaration of interest

Both C Boss and C Roch are full-time employees of Actelion Pharmaceuticals Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.