RESUMO
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Assuntos
Asma/tratamento farmacológico , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Asma/metabolismo , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Esteroides/farmacologia , Relação Estrutura-Atividade , Células U937RESUMO
Replacing the N-Boc-protecting group on a beta-amino organo-zinc reagent with a trifluoroacetyl group, which would be expected to make the nitrogen a better leaving group, results in a reagent that is more stable towards elimination.
RESUMO
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
Assuntos
Glucoquinase/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Ativação Enzimática , Feminino , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Tiazóis/efeitos adversos , Tiazóis/farmacocinéticaRESUMO
Palladium-catalysed reaction of unprotected 2-, 3-, and 4-iodophenols with a range of amino acid derived organozinc reagents (not used in excess) gives the expected products in good to excellent yield, demonstrating that carbon-zinc bonds are not protonated by acidic phenols under the conditions of palladium-catalysed coupling reactions.