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

Autor:	Claire E. Smith, Rossana Perciaccante, Peter R. Butchers, Alison J. Ford, Gillian Elizabeth Lunniss, Richard Conroy, Séverine Jeulin, Brian Edgar Looker, Graham Somers, Valerie S. Morrison, Amanda Emmons, Panayiotis A. Procopiou, Nicola Bevan, Victoria J. Barrett, Mark Ruston, Peter J. Mutch
Rok vydání:	2011
Předmět:	Organic Chemistry Clinical Biochemistry Pharmaceutical Science Hydantoin Adrenergic Uracil Pharmacology Biochemistry In vitro Bioavailability Guinea pig chemistry.chemical_compound chemistry In vivo Drug Discovery Microsome Molecular Medicine Molecular Biology
Zdroj:	Bioorganic & Medicinal Chemistry. 19:4192-4201
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2011.05.064
Popis:	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.
Databáze:	OpenAIRE
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