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Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists

Mistry, Shailesh N.; Baker, Jillian G.; Fischer, Peter M.; Hill, Stephen J.; Gardiner, Sheila M.; Kellam, Barrie

Authors

JILLIAN BARKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine

Peter M. Fischer peter.fischer@nottingham.ac.uk

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

Sheila M. Gardiner

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BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry



Abstract

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 β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). 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 β1- selectivity.

Citation

Mistry, S. N., Baker, J. G., Fischer, P. M., Hill, S. J., Gardiner, S. M., & Kellam, B. (2013). Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists. Journal of Medicinal Chemistry, 56(10), https://doi.org/10.1021/jm400348g

Journal Article Type Article
Acceptance Date Apr 1, 2013
Publication Date Apr 24, 2013
Deposit Date Sep 30, 2015
Publicly Available Date Sep 30, 2015
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 56
Issue 10
DOI https://doi.org/10.1021/jm400348g
Public URL http://eprints.nottingham.ac.uk/id/eprint/30316
Publisher URL http://pubs.acs.org/doi/abs/10.1021/jm400348g
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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