RESUMEN
Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Bifenilo/síntesis química , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/antagonistas & inhibidores , Tiofenos/síntesis química , Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Tiofenos/farmacologíaRESUMEN
Synthetic approaches to mixed ligand chelators on readily available t-butylphenol-formaldehyde oligomer, PFO, scaffolds were examined. In a promising approach, tris and tetraphenol oligomers were selectively mono or di protected using t-butyldiphenyl silyl chloride. The utility of these protected intermediates to prepare representative mixed PFO chelators, carrying ligands such as hydroxamic acid, 3,2-hydroxypyridinones and others was then demonstrated. The introduction of the ligand tethers onto the phenolic scaffold can be done sequentially under relatively mild conditions that tolerate the presence of other sensitive ligand groups. The differential reactivity of the disilyl derivative 20b, allowed stepwise introduction of two different ligands on the internal phenolic positions. This enabled the introduction of three different ligand groups of choice onto the tetra phenol platform.
RESUMEN
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacología , Animales , Humanos , Células Jurkat , Ratones , Modelos Moleculares , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Conformación Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
In the presence of allyl tri-n-butyltin--AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.