Journal of Medicinal Chemistry · 2006 · 43 citations · 29 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryLead OptimizationDrug-receptor InteractionsHormone ReceptorsLigand BindingPotency OptimizationReceptor PharmacologyStructure-activity Relationship AnalysisAgonist ActivityAntagonist PotencyPyrimidine AnalogsPyrimidine AnaloguesReceptor-ligand Binding AffinityStructure-based Lead DiscoveryStructure-based Ligand DesignStructure-guided Design
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.
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Molecular basis of agonism and antagonism in the oestrogen receptor
A.M. Brzozowski, A.C.W. Pike, Zbigniew Dauter et al. · Nature · 1997 · 3.3K citations