RESUMO
A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Astenia/tratamento farmacológico , Broncodilatadores/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacocinética , Albuterol/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Humanos , Masculino , Ratos , Xinafoato de Salmeterol , EstereoisomerismoRESUMO
A series of novel, potent and selective human ß(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.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Descoberta de Drogas , Hidantoínas/química , Uracila/química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo , Estereoisomerismo , Traqueia/efeitos dos fármacosRESUMO
The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure.
Assuntos
Pirimidinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/química , Amidas/síntese química , Amidas/química , Amidas/farmacocinética , Aminas/síntese química , Aminas/química , Aminas/farmacocinética , Animais , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Microssomos Hepáticos/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
A novel small molecule NPY Y2 antagonist (3) identified from high throughput screening is described. A subsequent SAR study and optimisation programme based around this molecule is also described, leading to the identification of potent and soluble pyridyl analogue 36.
