Journal of Medicinal Chemistry · 2003 · 54 citations · 4 references
PharmacyMedicinal ChemistryPharmacologyCombinatorial ChemistryDrug DiscoveryStructure-activity RelationshipsChemical Library DesignEnzyme InhibitionLead Compound DesignLead DiscoveryPotency OptimizationStructure-activity Relationship AnalysisChemical Library SynthesisCombinatorial Library ConstructionCombinatorial Library SynthesisEnzyme Inhibitor DiscoveryLead Compound OptimizationLead Compound ScreeningMedicinal Chemistry ApplicationsPiperidine Chemistry
A novel piperidine series of farnesyltransferase (FTase) inhibitors is described. Systematic medicinal chemistry studies starting with the lead compound, discovered from a 5-nitropiperidin-2-one combinatorial library, resulted in a potent series of novel FTase inhibitors. We found that all of four substituents of the piperidine core played an important role for FTase inhibition. A 10-fold increase in potency was observed by changing the piperidine-2-one core to the corresponding piperidine core. This class of compounds was found to inhibit farnesyltransferase in a Ras competitive manner. Optical resolution of several potent inhibitors revealed that the (+)-enantiomers showed potent farnesyltransferase inhibition. (+)-8 inhibited FTase with an IC(50) of 1.9 nM.
4