RESUMEN
Tackling PPIs, particularly by stabilizing clinically favored conformations of target proteins, with orally available, bona fide small molecules remains a significant but immensely worthwhile challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.
Asunto(s)
Diseño de Fármacos , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Descubrimiento de Drogas , Humanos , Unión Proteica , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.
Asunto(s)
Antineoplásicos/síntesis química , Productos Biológicos/síntesis química , Inmunosupresores/síntesis química , Sirolimus/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Ciclización , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Estructura Molecular , Sirolimus/química , Sirolimus/farmacologíaRESUMEN
The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated in the perception of pain. Here we describe the discovery and optimization of a small molecule agonist and initial docking studies of this ligand into the receptor in order to provide a suitable lead and tool compound for the elucidation of the physiological function of the receptor.
Asunto(s)
Piperazinas/síntesis química , Piridazinas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Calcio/metabolismo , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Piperazinas/farmacología , Piridazinas/farmacología , Receptores Acoplados a Proteínas G/fisiología , Relación Estructura-ActividadRESUMEN
The optimisation of a tertiary sulfonamide high-throughput screening hit is described. A combination of high-throughput chemistry, pharmacophore analysis and in silico PK profiling resulted in the discovery of potent sulfonamide oxytocin receptor antagonists with oral exposure and good selectivity over vasopressin receptors.
Asunto(s)
Descubrimiento de Drogas , Oxitocina/antagonistas & inhibidores , Sulfonamidas/farmacología , Administración Oral , Modelos Moleculares , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.