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Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists

[Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To...

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Autores principales: Mistry, Shailesh N., Baker, Jillian G, Fischer, Peter M, Hill, Stephen J, Gardiner, Sheila M, Kellam, Barrie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2013
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694353/
https://www.ncbi.nlm.nih.gov/pubmed/23614528
http://dx.doi.org/10.1021/jm400348g
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author Mistry, Shailesh N.
Baker, Jillian G
Fischer, Peter M
Hill, Stephen J
Gardiner, Sheila M
Kellam, Barrie
author_facet Mistry, Shailesh N.
Baker, Jillian G
Fischer, Peter M
Hill, Stephen J
Gardiner, Sheila M
Kellam, Barrie
author_sort Mistry, Shailesh N.
collection PubMed
description [Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β(1)-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β(1)-adrenoceptor selectivity and partial agonism (log K(D) of −7.75 and −5.15 as an antagonist of functional β(1)- and β(2)-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β(1))). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β(1)-selectivity.
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spelling pubmed-36943532013-06-28 Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists Mistry, Shailesh N. Baker, Jillian G Fischer, Peter M Hill, Stephen J Gardiner, Sheila M Kellam, Barrie J Med Chem [Image: see text] β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β(1)-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β(1)-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β(1)-adrenoceptor selectivity and partial agonism (log K(D) of −7.75 and −5.15 as an antagonist of functional β(1)- and β(2)-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β(1))). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β(1)-selectivity. American Chemical Society 2013-04-24 2013-05-23 /pmc/articles/PMC3694353/ /pubmed/23614528 http://dx.doi.org/10.1021/jm400348g Text en Copyright © 2013 American Chemical Society Terms of Use CC-BY (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
spellingShingle Mistry, Shailesh N.
Baker, Jillian G
Fischer, Peter M
Hill, Stephen J
Gardiner, Sheila M
Kellam, Barrie
Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title_full Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title_fullStr Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title_full_unstemmed Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title_short Synthesis and in Vitro and in Vivo Characterization of Highly β(1)-Selective β-Adrenoceptor Partial Agonists
title_sort synthesis and in vitro and in vivo characterization of highly β(1)-selective β-adrenoceptor partial agonists
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694353/
https://www.ncbi.nlm.nih.gov/pubmed/23614528
http://dx.doi.org/10.1021/jm400348g
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