Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.

Autor: Pinkerton AB; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Peddibhotla S; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Yamamoto F; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Slosky LM; Duke University Medical Center , Durham , North Carolina 27709 , United States., Bai Y; Duke University Medical Center , Durham , North Carolina 27709 , United States., Maloney P; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Hershberger P; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Hedrick MP; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Falter B; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Ardecky RJ; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Smith LH; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Chung TDY; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Jackson MR; Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States., Caron MG; Duke University Medical Center , Durham , North Carolina 27709 , United States., Barak LS; Duke University Medical Center , Durham , North Carolina 27709 , United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Sep 12; Vol. 62 (17), pp. 8357-8363. Date of Electronic Publication: 2019 Aug 20.
DOI: 10.1021/acs.jmedchem.9b00340
Abstrakt: Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.
Databáze: MEDLINE
Externí odkaz: