RESUMEN
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
Asunto(s)
Amidas/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Bibliotecas de Moléculas Pequeñas/química , Tiazoles/química , Enfermedades Autoinmunes/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Inflamación/tratamiento farmacológico , Interleucina-17/química , Modelos Moleculares , Estructura Molecular , Unión Proteica , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
Asunto(s)
Benzofuranos/química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/antagonistas & inhibidores , Animales , Benzofuranos/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
Efforts to improve the properties of the well studied ketooxazole FAAH inhibitor OL-135 resulted in the discovery of a novel propylpiperidine series of FAAH inhibitors that has a modular design and superior properties to OL-135. The efficacy of one of these compounds was demonstrated in a rat spinal nerve ligation model of neuropathic pain in rats.