ABSTRACT
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
Subject(s)
Antidepressive Agents/pharmacology , Indazoles/pharmacology , Neurokinin-1 Receptor Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Administration, Oral , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/toxicity , Depressive Disorder/drug therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Gerbillinae , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Indazoles/toxicity , Mice , Molecular Structure , Neurokinin-1 Receptor Antagonists/chemical synthesis , Neurokinin-1 Receptor Antagonists/chemistry , Neurokinin-1 Receptor Antagonists/toxicity , Rats , Receptors, Neurokinin-1/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/toxicity , Structure-Activity Relationship , Transcriptional Regulator ERG/metabolismABSTRACT
Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Neurokinin-1 Receptor Antagonists/chemistry , Neurokinin-1 Receptor Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Depression/drug therapy , Depression/metabolism , Gerbillinae , Humans , Neurokinin-1 Receptor Antagonists/pharmacokinetics , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacokineticsABSTRACT
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
