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
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
PDE5 inhibitors based upon the xanthine scaffold 8 have been expediently synthesized using a solid-phase route. Attachment of the xanthine scaffold 8 using the Rink chloride linker 4 and N-1 functionalization using Mitsunobu chemistry is described. A library of compounds was produced in multi-milligram quantities with excellent purities and acceptable yields. The compounds were tested for their PDE5 inhibitory activity.
Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Xantina/química , 3',5'-GMP Cíclico Fosfodiesterases , Técnicas de Química Combinatória , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Bases de Dados Factuais , Indicadores e Reagentes/química , Ressonância Magnética Nuclear Biomolecular , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Etanolaminas/química , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Albuterol/química , Animais , Etanolaminas/síntese química , Etanolaminas/farmacologia , Fumarato de Formoterol , Cobaias , Humanos , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Xinafoato de Salmeterol , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Xantinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/química , Xantinas/químicaRESUMO
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.