Journal of Enzyme Inhibition and Medicinal Chemistry · 2013 · 13 citations · 12 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryStructure-activity RelationshipsEnzyme InhibitionLigand BindingLigand-based DesignPotency OptimizationStructure-activity Relationship AnalysisStructure-based Pharmacophore ModelingBiological Evaluation ReportLigand-based Pharmacophore DesignLigand-based Pharmacophore ScreeningLigand-based ScreeningSar InterpretationStructure - Activity Relationship OptimizationStructure-based Ligand DesignStructure-based Pharmacophore Design
This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried. The combined structure- and ligand-based approaches culminated in a few analogs with either retained or slightly higher potency. The compounds which retained the potency were also checked for their ability to inhibit human peripheral blood mononuclear cells proliferation. This study illuminates the stringent structural requirements and strict SAR for IMPDH II inhibition.
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Steven L. Dixon, Alexander M. Smondyrev, Eric H. Knoll et al. · Journal of Computer-Aided Molecular Design · 2006 · 1.2K citations