Design driven HtL: The discovery and synthesis of new high efficacy β₂-agonists

Michael J Stocks; Lilian Alcaraz; Andrew Bailey; Roger Bonnert; Elaine Cadogan; Jadeen Christie; Stephen Connolly; Anthony Cook; Adrian Fisher; Alice Flaherty; Stephen Hill; Alexander Humphries; Anthony Ingall; Stephen Jordan; Mandy Lawson; Alex Mullen; David Nicholls; Stuart Paine; Garry Pairaudeau; Stephen St-Gallay; Alan Young

doi:10.1016/j.bmcl.2011.04.135

Design driven HtL: The discovery and synthesis of new high efficacy β₂-agonists

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4027-31. doi: 10.1016/j.bmcl.2011.04.135. Epub 2011 May 20.

Affiliation

¹ Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. [email protected]

PMID: 21652207
DOI: 10.1016/j.bmcl.2011.04.135

Abstract

The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

MeSH terms

Adrenergic beta-2 Receptor Agonists / chemical synthesis*
Adrenergic beta-2 Receptor Agonists / chemistry
Animals
Bronchi / cytology
Cell Line
Crystallography, X-Ray
Drug Design*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Adrenergic beta-2 Receptor Agonists