RESUMO
The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing α-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzotiazóis/administração & dosagem , Benzotiazóis/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Benzotiazóis/química , Relação Dose-Resposta a Droga , Cobaias , Estrutura MolecularRESUMO
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
A particular problem with the release of dense nonaqueous phase liquids (DNAPLs) into the environment is identifying where the DNAPL is and if it is still moving. This question is particularly important at sites where thousands of cubic meters of DNAPLs were disposed of. To date, results from laboratory models have not been scaled to predict analogous migration at the larger length and time scales appropriate for sites where large volumes of DNAPLs were released. Modified inspectional analysis is a technique for developing scaling relationships through nondimensionalizing the governing equations. It was applied in this study to scale observations of DNAPL migration in a laboratory model to four hypothetical scenarios in the field where large volumes of DNAPL were released. One scenario was compared to a large DNAPL spill site. The length and time scales of DNAPL movement predicted from our analysis are consistent with those predicted from a numerical model of this site. To our knowledge, this is the first application of modified inspectional analysis for release of DNAPLs in a laboratory model. This methodology may prove useful for scaling results from other laboratory investigations of DNAPL migration to field-scale systems.
Assuntos
Resíduos Perigosos , Modelos Teóricos , Gerenciamento de Resíduos/métodos , Poluentes Químicos da Água , HumanosRESUMO
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
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.