The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.

Autor: Procopiou PA; Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com, Barrett VJ, Bevan NJ, Butchers PR, Conroy R, Emmons A, Ford AJ, Jeulin S, Looker BE, Lunniss GE, Morrison VS, Mutch PJ, Perciaccante R, Ruston M, Smith CE, Somers G
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2011 Jul 15; Vol. 19 (14), pp. 4192-201. Date of Electronic Publication: 2011 Jun 21.
DOI: 10.1016/j.bmc.2011.05.064
Abstrakt: A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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