RESUMEN
Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration.
Asunto(s)
Técnicas Químicas Combinatorias , Diseño Asistido por Computadora , Bases de Datos Factuales , Internet , Bibliotecas Digitales , Estructura MolecularRESUMEN
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Asunto(s)
Androstadienos/síntesis química , Androstadienos/farmacología , Receptor beta de Estrógeno/agonistas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstadienos/química , Animales , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Receptores Androgénicos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/químicaRESUMEN
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Indoles/química , Indoles/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Útero/efectos de los fármacosRESUMEN
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Asunto(s)
Androstenodioles/síntesis química , Receptor beta de Estrógeno/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodioles/farmacología , Ciclización , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Asunto(s)
Androstenodiol/análogos & derivados , Androstenodiol/farmacología , Receptor beta de Estrógeno/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodiol/síntesis química , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Reagent Selector is an intranet-based tool that aids in the selection of reagents for use in combinatorial library construction. The user selects an appropriate reagent group as a query, for example, primary amines, and further refines it on the basis of various physicochemical properties, resulting in a list of potential reagents. The results of this selection process are, in turn, converted into synthons: the fragments or R-groups that are to be incorporated into the combinatorial library. The Synthon Analysis interface graphically depicts the chemical properties for each synthon as a function of the topological bond distance from the scaffold attachment point. Displayed in this fashion, the user is able to visualize the property space for the universe of synthons as well as that of the synthons selected. Ultimately, the reagent list that embodies the selected synthons is made available to the user for reagent procurement. Application of the approach to a sample reagent list for a G-protein coupled receptor targeted library is described.