Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression

• Published in: Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (2), p.407-411
• Main Authors: Gillman, Kevin W., Parker, Michael F., Silva, Mark, Degnan, Andrew P., Tora, George O., Lodge, Nicholas J., Li, Yu-Wen, Lelas, Snjezana, Taber, Matthew, Krause, Rudolf G., Bertekap, Robert L., Newton, Amy E., Pieschl, Rick L., Lengyel, Kelly D., Johnson, Kim A., Taylor, Sarah J., Bronson, Joanne J., Macor, John E.
• Format: Article
• Language: English
• Subjects: Animals; chemistry; Data processing; Depression; Depression - drug therapy; Disease Models, Animal; Drug Design; Ethers; Gerbillinae; gerbils; in vivo studies; Inhibitory Concentration 50; Ion channels; Molecular Structure; Neurokinin 1 antagonists; Neurokinin-1 Receptor Antagonists; pyridines; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - therapeutic use; Receptor occupancy; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - therapeutic use; Serotonin transporter; Serotonin transporter inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.094

A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK1/SERT affinity. Optimization based on NK1/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 NK1/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.