RESUMO
A series of novel, potent, and selective human ß2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no ß2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Sulfonas/síntese química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Esquema de Medicação , Descoberta de Drogas , Cobaias , Hepatócitos/metabolismo , Humanos , Ratos , Sulfonas/metabolismo , Sulfonas/farmacologia , Traqueia/efeitos dos fármacosRESUMO
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
A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/metabolismo , Animais , Álcool Benzílico/química , Álcoois Benzílicos/síntese química , Álcoois Benzílicos/química , Álcoois Benzílicos/metabolismo , Álcoois Benzílicos/farmacologia , Células CHO , Clorobenzenos/síntese química , Clorobenzenos/química , Clorobenzenos/metabolismo , Clorobenzenos/farmacologia , Cricetinae , Cricetulus , Humanos , Modelos Moleculares , Conformação Proteica , Ratos , Receptores Adrenérgicos beta 2/química , Relação Estrutura-AtividadeRESUMO
A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
Assuntos
2-Hidroxifenetilamina/análogos & derivados , Agonistas de Receptores Adrenérgicos beta 2 , Sulfonamidas/síntese química , 2-Hidroxifenetilamina/síntese química , 2-Hidroxifenetilamina/química , 2-Hidroxifenetilamina/farmacologia , Administração Oral , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacologia , Animais , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Cães , Cobaias , Humanos , Técnicas In Vitro , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Xinafoato de Salmeterol , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
The pharmacological properties of the novel ligand, (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol (I), at the human adenosine receptors were investigated using Chinese hamster ovary cell lines recombinantly expressing these receptors. Functional studies were performed using a cyclic AMP-coupled reporter gene system. Binding studies were performed using membranes from these cells. The effects of ligand (I) were also determined on functional responses of human neutrophils and eosinophils. Ligand (I) had a high affinity for the adenosine A(2A) receptor (pKi 7.8+/-0.2) and was a potent agonist at this receptor (pEC(50) 9.0+/-0.2). Ligand (I) had a similar affinity for the adenosine A(3) receptor (pKi 7.8+/-0.1) but displayed no agonist activity, acting instead as a competitive antagonist (pA(2) 8.3+/-0.04). Ligand (I) had lower affinity for adenosine A(1) and A(2B) receptors (pKi=6) and showed relatively weak agonist activity at these receptors (pEC(50) 7.1 at both receptors). Ligand (I) was a potent inhibitor of the generation of reactive oxygen species from human neutrophils and eosinophils (pEC(50) 9.7+/-0.1 and 9.4+/-0.2 respectively). The inhibitory effect of ligand (I) on the release of reactive oxygen species from neutrophils was antagonised competitively by the adenosine A(2A) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) with a pA(2) value (10.03+/-0.44) consistent with an effect on adenosine A(2A) receptors. Ligand (I) also inhibited the release of granule proteins from neutrophils and eosinophils (pEC(50) 8.7 and 8.9 respectively), albeit less potently than as an inhibitor of reactive oxygen species generation. In summary, ligand (I) is a potent and selective agonist for the adenosine A(2A) receptor and a competitive antagonist at the adenosine A(3) receptor. Ligand (I) has potent anti-inflammatory effects on human granulocytes in vitro.