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

Anthony B. Pinkerton; Satyamaheshwar Peddibhotla; Fusayo Yamamoto; Lauren M. Slosky; Yushi Bai; Patrick Maloney; Paul Hershberger; Michael P. Hedrick; Bekhi Falter; Robert J. Ardecky; Layton H. Smith; Thomas D.Y. Chung; Michael R. Jackson; Marc G. Caron; Lawrence S. Barak

doi:10.1021/acs.jmedchem.9b00340

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

Anthony B. Pinkerton
, Satyamaheshwar Peddibhotla
, Fusayo Yamamoto
, Lauren M. Slosky
, Yushi Bai
, Patrick Maloney
, Paul Hershberger
, Michael P. Hedrick
, Bekhi Falter
, Robert J. Ardecky
, Layton H. Smith
, Thomas D.Y. Chung
, Michael R. Jackson
, Marc G. Caron
, Lawrence S. Barak

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English (US)
Pages (from-to)	8357-8363
Number of pages	7
Journal	Journal of medicinal chemistry
Volume	62
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00340
State	Published - Sep 12 2019
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants R21/33 DA038019 to A.B.P. and 5P30DA029925 to M.G.C. and L.S.B. We acknowledge Peter Wilson at Almac, Craigavon, United Kingdom, for scale up work on 18 , WuXi, Shanghai, China, for measurements of the PK parameters, Eurofins, Taipei, Taiwan, for the binding studies in Figure 3, and Alexander Braddock and Emmanuel Theodorakis at the University of California, San Diego, for assistance with measuring optical rotations.

Publisher Copyright:
© 2019 American Chemical Society.

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10.1021/acs.jmedchem.9b00340

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Pinkerton, A. B., Peddibhotla, S., Yamamoto, F., Slosky, L. M., Bai, Y., Maloney, P., Hershberger, P., Hedrick, M. P., Falter, B., Ardecky, R. J., Smith, L. H., Chung, T. D. Y., Jackson, M. R., Caron, M. G., & Barak, L. S. (2019). Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators. Journal of medicinal chemistry, 62(17), 8357-8363. https://doi.org/10.1021/acs.jmedchem.9b00340

Pinkerton, AB, Peddibhotla, S, Yamamoto, F, Slosky, LM, Bai, Y, Maloney, P, Hershberger, P, Hedrick, MP, Falter, B, Ardecky, RJ, Smith, LH, Chung, TDY, Jackson, MR, Caron, MG & Barak, LS 2019, 'Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators', Journal of medicinal chemistry, vol. 62, no. 17, pp. 8357-8363. https://doi.org/10.1021/acs.jmedchem.9b00340

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title = "Discovery of β-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.",

author = "Pinkerton, \{Anthony B.\} and Satyamaheshwar Peddibhotla and Fusayo Yamamoto and Slosky, \{Lauren M.\} and Yushi Bai and Patrick Maloney and Paul Hershberger and Hedrick, \{Michael P.\} and Bekhi Falter and Ardecky, \{Robert J.\} and Smith, \{Layton H.\} and Chung, \{Thomas D.Y.\} and Jackson, \{Michael R.\} and Caron, \{Marc G.\} and Barak, \{Lawrence S.\}",

note = "Funding Information: This work was supported by National Institutes of Health grants R21/33 DA038019 to A.B.P. and 5P30DA029925 to M.G.C. and L.S.B. We acknowledge Peter Wilson at Almac, Craigavon, United Kingdom, for scale up work on 18 , WuXi, Shanghai, China, for measurements of the PK parameters, Eurofins, Taipei, Taiwan, for the binding studies in Figure 3, and Alexander Braddock and Emmanuel Theodorakis at the University of California, San Diego, for assistance with measuring optical rotations. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

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AU - Peddibhotla, Satyamaheshwar

AU - Yamamoto, Fusayo

AU - Slosky, Lauren M.

AU - Bai, Yushi

AU - Maloney, Patrick

AU - Hershberger, Paul

AU - Hedrick, Michael P.

AU - Falter, Bekhi

AU - Ardecky, Robert J.

AU - Smith, Layton H.

AU - Chung, Thomas D.Y.

AU - Jackson, Michael R.

AU - Caron, Marc G.

AU - Barak, Lawrence S.

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AB - 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.

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

Abstract

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