RESUMEN
A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Química Farmacéutica/métodos , Proteínas Hedgehog/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/farmacología , Línea Celular , Diseño de Fármacos , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Modelos Biológicos , Modelos Químicos , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Asunto(s)
Amidas/química , Anilidas/química , Proteínas Hedgehog/metabolismo , Piridinas/química , Amidas/síntesis química , Amidas/farmacología , Anilidas/síntesis química , Anilidas/farmacología , Animales , Bencimidazoles/química , Carcinoma Basocelular/tratamiento farmacológico , Línea Celular , Neoplasias Cerebelosas/tratamiento farmacológico , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Meduloblastoma/tratamiento farmacológico , Ratones , Ratones Desnudos , Piridinas/síntesis química , Piridinas/farmacología , Transducción de Señal , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A small family of phenyl quinazolinone ureas is reported as potent modulators of Hedgehog protein function. Preliminary SAR studies of the urea substituent led to a nanomolar Hedgehog antagonist.