Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists

Hui Xiong; James Kang; James M Woods; John P McCauley Jr; Gerard M Koether; Jeffrey S Albert; Lindsay Hinkley; Yan Li; Reto A Gadient; Thomas R Simpson

doi:10.1016/j.bmcl.2010.11.003

Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1896-9. doi: 10.1016/j.bmcl.2010.11.003. Epub 2010 Dec 21.

Authors

Hui Xiong¹, James Kang, James M Woods, John P McCauley Jr, Gerard M Koether, Jeffrey S Albert, Lindsay Hinkley, Yan Li, Reto A Gadient, Thomas R Simpson

Affiliation

¹ CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, DE, USA.

PMID: 21320776
DOI: 10.1016/j.bmcl.2010.11.003

Abstract

The neurokinin-3 (NK3) receptor is regarded as a potential novel target for treating patients with schizophrenia. Herein we report the synthesis and SAR of a series of C3-alkylsulfoxide substituted quinolines as potent NK3 receptor antagonists. These compounds have excellent NK3 functional activity, good selectivity and drug-like properties. Several key compounds have good in vitro/in vivo DMPK characteristics, and are active in a gerbil locomotor activity model.

MeSH terms

Animals
Gerbillinae
Motor Activity / drug effects
Quinolines / chemistry*
Quinolines / pharmacology*
Receptors, Neurokinin-3 / antagonists & inhibitors*
Structure-Activity Relationship
Sulfoxides / chemistry*

Substances

Quinolines
Receptors, Neurokinin-3
Sulfoxides