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

ABSTRACT: 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.

SUBMITTER: Pinkerton AB

PROVIDER: S-EPMC7003992 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Pinkerton Anthony B AB Peddibhotla Satyamaheshwar S Yamamoto Fusayo F Slosky Lauren M LM Bai Yushi Y Maloney Patrick P Hershberger Paul P Hedrick Michael P MP Falter Bekhi B Ardecky Robert J RJ Smith Layton H LH Chung Thomas D Y TDY Jackson Michael R MR Caron Marc G MG Barak Lawrence S LS

Journal of medicinal chemistry 20190820 17

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 <b>18</b> (SBI-553), a potent and brain penetrant NTR1 allosteric modulator. ...[more]

PMID: 31390201

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