RESUMEN
The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.
Asunto(s)
Amitrol (Herbicida)/química , Amitrol (Herbicida)/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Triazoles/química , Triazoles/uso terapéutico , Amitrol (Herbicida)/farmacología , Animales , Antineoplásicos/farmacología , Cristalografía por Rayos X , Humanos , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
Asunto(s)
Dimensión del Dolor/métodos , Canal Catiónico TRPA1/agonistas , Canal Catiónico TRPA1/metabolismo , Secuencia de Aminoácidos , Animales , Femenino , Células HEK293 , Humanos , Ligandos , Masculino , Dimensión del Dolor/efectos de los fármacos , Estructura Secundaria de Proteína , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Canal Catiónico TRPA1/químicaRESUMEN
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.