The discovery of long-acting saligenin beta(2) adrenergic receptor agonists incorporating hydantoin or uracil rings.

Article Details

Citation

Procopiou PA, 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

The discovery of long-acting saligenin beta(2) adrenergic receptor agonists incorporating hydantoin or uracil rings.

Bioorg Med Chem. 2011 Jul 15;19(14):4192-201. doi: 10.1016/j.bmc.2011.05.064. Epub 2011 Jun 21.

PubMed ID
21696967 [ View in PubMed
]
Abstract

A series of novel, potent and selective human beta(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 muM. 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
IsoprenalineBeta-1 adrenergic receptorEC 50 (nM)7.94N/AN/ADetails
IsoprenalineBeta-3 adrenergic receptorEC 50 (nM)39.81N/AN/ADetails
SalmeterolBeta-1 adrenergic receptorEC 50 (nM)794.33N/AN/ADetails
SalmeterolBeta-3 adrenergic receptorEC 50 (nM)1258.93N/AN/ADetails