Tachykinin neurokinin 3 receptor antagonists: a patent review (2005-2010)

Introduction: The neurokinin 3 (NK3) receptor is a GPCR that has been shown to modulate monoaminergic systems within regions of the brain implicated in schizophrenia. Preclinical and Phase II clinical results of osanetant and talnetant in schizophrenic patients have indicated that NK3 antagonists may provide significant improvement of the positive symptoms and cognitive impairment associated with this disorder. Recent findings have also indicated that neurokinin B (NKB)-NK3 signaling plays a key role in the hypothalamic regulation of reproduction in humans. Areas covered: This review article discusses the latest medicinal chemistry strategies used to derive novel NK3 receptor antagonists which have been patented during the period 2005 - 2010. Expert opinion: Since the report of a beneficial effect of osanetant in schizophrenic patients, major pharmaceutical companies have been involved in this field, leading to a very large number of patent applications disclosed. Nevertheless, only three NK3 selective antagonists entered into Phase II, but were then terminated for various reasons. Currently, the main challenge to move forward a selective NK3 antagonist into the clinic would be to define a safety margin between the desired therapeutic effect and the effect on testosterone levels. The involvement of NKB-NK3 signaling in reproduction in humans may also lead to new exciting indications, such as treatment for sex steroid-sensitive cancers of breast and prostate.