RESUMEN
Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4â¯t limited ghrelin-induced food intake.
Asunto(s)
Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/farmacología , Enlace de Hidrógeno , Indoles/química , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Mutagénesis , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.
Asunto(s)
Receptores Nucleares Huérfanos/antagonistas & inhibidores , Sulfonamidas/síntesis química , Animales , Línea Celular , Cristalografía por Rayos X , Haplorrinos , Humanos , Receptores X del Hígado , Modelos Moleculares , Receptores Nucleares Huérfanos/genética , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.