RESUMO
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
Assuntos
Ácidos Cicloexanocarboxílicos/química , Naftiridinas/química , Inibidores da Fosfodiesterase 4/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Náusea/induzido quimicamente , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Termodinâmica , Vômito/induzido quimicamenteRESUMO
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Assuntos
Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Ratos , Solubilidade , Vômito/tratamento farmacológicoRESUMO
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/química , Indanos/farmacologia , Quinolonas/farmacologia , Administração por Inalação , Animais , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indanos/administração & dosagem , Indanos/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
Assuntos
Acetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/química , Animais , Disponibilidade Biológica , Eosinófilos/efeitos dos fármacos , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Xantinas/farmacologia , Animais , Disponibilidade Biológica , Bovinos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Masculino , Farmacocinética , Isoformas de Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade , Xantinas/químicaRESUMO
The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Receptor A2B de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Tiazóis , Animais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
A series of novel corticosteroid derivatives featuring C-17 furoate ester functionality have been synthesised. Profiling in vitro and in vivo has resulted in the identification of a compound with a longer duration of action and a lower oral side effect profile in rodents compared to budesonide.