RESUMEN
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
Asunto(s)
Antipsicóticos/química , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Triazoles/química , Regulación Alostérica/efectos de los fármacos , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Microsomas/metabolismo , Ratas , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-Actividad , Triazoles/metabolismo , Triazoles/farmacologíaRESUMEN
We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.