Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications.
The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor (mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates.
Simonsen
Klaus B
KB
Lundbeck Research DK, Valby, Denmark. KBSI@lundbeck.com
Juhl
Karsten
K
Steiniger-Brach
Björn
B
Nielsen
Søren Møller
SM
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology*
D014150:Antipsychotic Agents; D018042:Receptors, Neurokinin-3