RESUMEN
2,3-Diarylpyrazolo[1,5-a]pyrimidines are estrogen receptor (ER) antagonists of modest potency that we have described previously. Guided by the crystal structure of an ER-ligand complex that we have obtained with one of these compounds, we prepared analogs that contain a basic side chain at the 2- or 3-aryl group and quickly found one that, according to the structure-based prediction, shows an increase in binding affinity and antagonist potency and a loss of residual agonist activity.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Línea Celular Tumoral , Cristalografía por Rayos X , Receptor alfa de Estrógeno/química , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERbeta. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERbeta in binding. Curiously, on the basis of molecular modeling, the ERbeta binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERalpha vs ERbeta. In transcription assays this pyrazolopyrimidine was fully effective as an ERbeta antagonist while exhibiting no significant activity on ERalpha. Thus, this ligand functions as a potency- and efficacy-selective ERbeta antagonist that would abrogate estrogen action through ERbeta with minimal effects on its activity through ERalpha; as such, it could be used to study the biological function of ERbeta.
Asunto(s)
Receptor beta de Estrógeno/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Unión Competitiva , Línea Celular Tumoral , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Humanos , Ligandos , Modelos Moleculares , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , TransfecciónRESUMEN
This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.
RESUMEN
We have examined the pyrazolo[1,5-a]pyrimidine scaffold as a novel core structure for estrogen receptor ligands. Attachment of various substituents has helped to define the orientation of this heterocycle in the ligand-binding pocket as one in which a pendant phenol rather than the hydroxylpyrimidine serves as a mimic of the A-ring of estradiol.