RESUMO
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Assuntos
Amidas/farmacologia , Carbazóis/farmacologia , Criptocromos/metabolismo , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Ureia/farmacologia , Amidas/síntese química , Amidas/química , Animais , Carbazóis/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
Assuntos
Carbazóis/química , Criptocromos/química , Hipoglicemiantes/química , Sulfonamidas/química , Animais , Glicemia/análise , Linhagem Celular Tumoral , Criptocromos/genética , Criptocromos/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
Narcolepsy type 1 (Na-1) and 2 (Na-2) are characterized by an inability to sustain wakefulness and are likely caused by degeneration of orexin neurons. Near complete orexin neurodegeneration depletes orexin-A from the cerebrospinal fluid and produces Na-1. The pathophysiology of Na-2 is less understood but has been hypothesized to be due to less extensive loss of orexin neurotransmission. The orexin-tTA; TetO diphtheria toxin A mouse allows conditional control over the extent and timing of orexin neurodegeneration. To evaluate partial ablation of the orexin field as a model of Na-2, orexin-A positive cell counts and sleep/wake phenotypes (determined by piezoelectric monitoring) were correlated within individual mice after different protocols of diet-controlled neurodegeneration. Partial ablations that began during the first 8 days of study were 14% larger than partial ablations induced during the last 8 days of study, 6 weeks later and prior to sacrifice of all mice, suggesting orexin-A positive cell death continued despite the resumption of conditions intended to keep orexin neurons intact. Sleep/wake of mice with 71.0% orexin-A positive cell loss, initiated at the beginning of study, resembled that of orexin-intact controls more than mice with near complete neurodegeneration. Conversely, mice with 56.6% orexin-A positive cell loss, created at the end of study, had sleep/wake phenotypes that were similar to those of mice with near complete orexin-A positive cell loss. Collectively, these results suggest that compensatory wake-promotion develops in mice that have some critical portion of their orexinergic system remaining after partial ablation.