Chiral dihydrobenzofuran acids show potent retinoid X receptor-nuclear receptor related 1 protein dimer activation

H. Sundén; A. Schäfer; M. Scheepstra; S. Leysen; M. Malo; Jian-Nong Ma; E.S. Burstein; Chr. Ottmann; L. Brunsveld; R. Olsson

doi:10.1021/acs.jmedchem.5b01702

Chiral dihydrobenzofuran acids show potent retinoid X receptor-nuclear receptor related 1 protein dimer activation

H. Sundén, A. Schäfer, M. Scheepstra, S. Leysen, M. Malo, Jian-Nong Ma, E.S. Burstein, Chr. Ottmann, L. Brunsveld, R. Olsson

Chemical Biology

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Abstract

The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

Original language	English
Pages (from-to)	1232-1238
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	3
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01702
Publication status	Published - 11 Feb 2016

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title = "Chiral dihydrobenzofuran acids show potent retinoid X receptor-nuclear receptor related 1 protein dimer activation",

abstract = "The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.",

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doi = "10.1021/acs.jmedchem.5b01702",

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T1 - Chiral dihydrobenzofuran acids show potent retinoid X receptor-nuclear receptor related 1 protein dimer activation

AU - Sundén, H.

AU - Schäfer, A.

AU - Scheepstra, M.

AU - Leysen, S.

AU - Malo, M.

AU - Ma, Jian-Nong

AU - Burstein, E.S.

AU - Ottmann, Chr.

AU - Brunsveld, L.

AU - Olsson, R.

PY - 2016/2/11

Y1 - 2016/2/11

N2 - The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

AB - The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.

U2 - 10.1021/acs.jmedchem.5b01702

DO - 10.1021/acs.jmedchem.5b01702

M3 - Article

C2 - 26820900

SN - 0022-2623

VL - 59

SP - 1232

EP - 1238

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -

Chiral dihydrobenzofuran acids show potent retinoid X receptor-nuclear receptor related 1 protein dimer activation

Abstract

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