RESUMEN
The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Quinazolinas/química , Quinazolinas/farmacología , Receptores de Vasopresinas/metabolismo , Acetamidas/síntesis química , Animales , Trastorno Depresivo/tratamiento farmacológico , Humanos , Quinazolinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Indoles/química , Indoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Animales , Bencimidazoles/metabolismo , Bencimidazoles/farmacocinética , Humanos , Hipotermia/inducido químicamente , Hipotermia/tratamiento farmacológico , Indoles/metabolismo , Indoles/farmacocinética , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Obesidad/tratamiento farmacológico , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.