RESUMEN
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Quinazolinas/química , Receptor de Adenosina A2A/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Animales , Sitios de Unión , Diseño de Fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Ratas , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/química , Prolina/análogos & derivados , Quinolinas/síntesis química , Administración Oral , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Inhalación , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacocinética , Prolina/síntesis química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Asunto(s)
Antiinflamatorios/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/síntesis química , Inhibidores de Fosfodiesterasa 4/síntesis química , Quinolinas/síntesis química , Animales , Antiinflamatorios/farmacología , Óxidos N-Cíclicos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Oxazoles/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Asunto(s)
Antifúngicos/química , Inhibidores Enzimáticos/química , Glucosiltransferasas/antagonistas & inhibidores , Plomo/química , Piperazinas/química , Piridazinas/química , Compuestos de Sulfonilurea/química , Animales , Antifúngicos/farmacología , Candida/efectos de los fármacos , Línea Celular , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Piperazina , Piridazinas/farmacología , Ratas , Relación Estructura-Actividad , Compuestos de Sulfonilurea/farmacologíaRESUMEN
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Asunto(s)
Antifúngicos/química , Inhibidores Enzimáticos/química , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Sulfonamidas/química , Animales , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Glucosiltransferasas/metabolismo , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Asunto(s)
Antifúngicos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Animales , Antifúngicos/química , Candida glabrata/efectos de los fármacos , Candida glabrata/enzimología , Candida glabrata/patogenicidad , Candidiasis/tratamiento farmacológico , Masculino , Ratones , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimologíaRESUMEN
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Piridazinas/farmacología , Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Relación Estructura-ActividadRESUMEN
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/síntesis química , Piridazinas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Inhibidores Enzimáticos/química , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
A structurally-diverse series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-one 1,1 dioxide scaffold were synthesized and used to probe the S' subsites of human neutrophil elastase (HNE) and neutrophil proteinase 3 (Pr 3). Several compounds are potent inhibitors of HNE but devoid of inhibitory activity toward Pr 3, suggesting that the S' subsites of HNE exhibit significant plasticity and can, unlike Pr 3, tolerate various large hydrophobic groups. The results provide a promising framework for the design of highly selective inhibitors of the two enzymes.
Asunto(s)
Elastasa de Leucocito/antagonistas & inhibidores , Inhibidores de Proteasas/química , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Humanos , Cinética , Elastasa de Leucocito/metabolismo , Mieloblastina/antagonistas & inhibidores , Mieloblastina/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.