RESUMEN
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 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
An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.
Asunto(s)
Isoquinolinas/química , Isoquinolinas/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Estereoisomerismo , Especificidad por Sustrato , Tirosina/químicaRESUMEN
A simple protocol for the synthesis of Weinreb benzamides and alpha,beta-unsaturated Weinreb amides through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-methoxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of potassium organotrifluoroborates.