Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression

Andrew P Degnan; George O Tora; Hong Huang; David A Conlon; Carl D Davis; Umesh M Hanumegowda; Xiaoping Hou; Yi Hsiao; Joanna Hu; Rudolph Krause; Yu-Wen Li; Amy E Newton; Rick L Pieschl; Joseph Raybon; Thorsten Rosner; Jung-Hui Sun; Matthew T Taber; Sarah J Taylor; Michael K Wong; Huiping Zhang; Nicholas J Lodge; Joanne J Bronson; John E Macor; Kevin W Gillman

doi:10.1021/acschemneuro.6b00337

Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression

ACS Chem Neurosci. 2016 Dec 21;7(12):1635-1640. doi: 10.1021/acschemneuro.6b00337. Epub 2016 Oct 18.

Authors

Andrew P Degnan¹, George O Tora¹, Hong Huang¹, David A Conlon², Carl D Davis¹, Umesh M Hanumegowda¹, Xiaoping Hou³, Yi Hsiao², Joanna Hu¹, Rudolph Krause¹, Yu-Wen Li¹, Amy E Newton¹, Rick L Pieschl¹, Joseph Raybon¹, Thorsten Rosner², Jung-Hui Sun³, Matthew T Taber¹, Sarah J Taylor¹, Michael K Wong³, Huiping Zhang³, Nicholas J Lodge¹, Joanne J Bronson¹, John E Macor¹, Kevin W Gillman¹

Affiliations

¹ Research and Development, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
² Chemical Development, Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.
³ Department of Chemical Synthesis, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.

PMID: 27744678
DOI: 10.1021/acschemneuro.6b00337

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.

Keywords: Depression; asymmetric hydrogenation; hERG; ion channels; neurokinin 1; serotonin transporter inhibitor.

MeSH terms

Administration, Oral
Animals
Antidepressive Agents / chemical synthesis
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
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 / pharmacology*
Indazoles / toxicity
Mice
Molecular Structure
Neurokinin-1 Receptor Antagonists / chemical synthesis
Neurokinin-1 Receptor Antagonists / chemistry
Neurokinin-1 Receptor Antagonists / pharmacology*
Neurokinin-1 Receptor Antagonists / toxicity
Rats
Receptors, Neurokinin-1 / metabolism
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology*
Selective Serotonin Reuptake Inhibitors / toxicity
Serotonin Plasma Membrane Transport Proteins / metabolism
Structure-Activity Relationship
Transcriptional Regulator ERG / metabolism

Substances

Antidepressive Agents
ERG protein, human
Indazoles
Neurokinin-1 Receptor Antagonists
Receptors, Neurokinin-1
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Transcriptional Regulator ERG