Difluoroethylpyridine derivatives as NR2B NMDA receptor antagonists

Abstract

Disclosed are chemical entities of formula (I) wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.

Description

Background technique [0001] Nonselective NMDA receptor antagonists originally developed in stroke and head trauma have recently shown clinical efficacy in the treatment of depression. The nonselective NMDA receptor antagonist ketamine has been shown to have rapid onset and efficacy in depression resistant to standard monoamine reuptake inhibitor therapy (Mathews and Zarate, 2013 , J. Clin. Psychiatry 74:516-158). However, non-selective NMDA receptor antagonists such as ketamine have a range of undesired pharmacological activities that limit their use in humans. In particular, dissociative or psychoactive side effects are particularly pronounced for non-selective NMDA receptor antagonists. Recently, NR2B subtype-selective NMDA receptor antagonists have demonstrated potential in a broad range of clinical indications. In particular, NR2B antagonists have also demonstrated antidepressant activity in early clinical trials (Ibrahim et al., 2012, J.Clin.Psychopharmacol. 32, 551-55...

AI Technical Summary

Problems solved by technology

However, NR2B antagonists described to date generally exhibit disadvantages in other drug properties, limiting potential use in human drug therapy

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