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Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1

Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1
Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1
We report the identification of substituted cis-bicyclo[3.3.0]oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.
0022-2623
6652-6655
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Dixon, Sally
943160fc-1b70-4c29-b2e3-b7785cee8a0c
Maloney, Patrick R.
4ad320c3-6cc2-4597-a63c-60bfc72c14e9
Delerive, Philippe
71e21ec1-b377-4a62-bb06-5567371c9b0b
Goodwin, Bryan J.
98ff110e-e718-40f7-a564-bf3cf0af9080
Parks, Derek J.
c9cd50cf-80e7-42b5-9581-a1ec6aa02410
Willson, Timothy M.
8b58e5d4-f941-4897-8e1c-1ec2aee8ad88
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Dixon, Sally
943160fc-1b70-4c29-b2e3-b7785cee8a0c
Maloney, Patrick R.
4ad320c3-6cc2-4597-a63c-60bfc72c14e9
Delerive, Philippe
71e21ec1-b377-4a62-bb06-5567371c9b0b
Goodwin, Bryan J.
98ff110e-e718-40f7-a564-bf3cf0af9080
Parks, Derek J.
c9cd50cf-80e7-42b5-9581-a1ec6aa02410
Willson, Timothy M.
8b58e5d4-f941-4897-8e1c-1ec2aee8ad88

Whitby, Richard J., Dixon, Sally, Maloney, Patrick R., Delerive, Philippe, Goodwin, Bryan J., Parks, Derek J. and Willson, Timothy M. (2006) Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1. Journal of Medicinal Chemistry, 49 (23), 6652-6655. (doi:10.1021/jm060990k).

Record type: Article

Abstract

We report the identification of substituted cis-bicyclo[3.3.0]oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.

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Published date: 2006

Identifiers

Local EPrints ID: 44084
URI: http://eprints.soton.ac.uk/id/eprint/44084
ISSN: 0022-2623
PURE UUID: eccb53e9-272a-4889-8a5b-9e77e9da3216
ORCID for Richard J. Whitby: ORCID iD orcid.org/0000-0002-9891-5502
ORCID for Sally Dixon: ORCID iD orcid.org/0000-0003-2219-3635

Catalogue record

Date deposited: 13 Feb 2007
Last modified: 29 Oct 2019 02:11

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