ABSTRACT

Abstract................................................................................................................... 166 Introduction............................................................................................................ 166 Screening.System.for.CYP11B2.Inhibitors............................................................ 167 Hit-Finding.Strategies............................................................................................ 168 Structure-Activity.Relationships........................................................................... 169 Molecular.Modeling.Studies.................................................................................. 169 Validation.of.the.Pharmacophore.Model............................................................... 172 In Vivo Activity-Proof.of.Concept....................................................................... 172 Conclusion.............................................................................................................. 173 References............................................................................................................... 173

Pathophysiological.and.clinical.studies.have.demonstrated.that.aldosterone.plays.a. detrimental.role.in.congestive.heart.failure.(CHF).and.myocardial.fibrosis..We.have. identified. aldosterone. synthase. (CYP11B2). as. a. novel. target. for. the. treatment. of. these.diseases..Using.our. focused.compound. library-more. than.500.compounds. that.earlier.had.been.synthesized.as.inhibitors.of.selected.CYP.enzymes-we.identified. hits,. which. were. further. optimized. structurally.. Thus,. potent. and. selective. inhibitors.of.CYP11B2.were.discovered..Further.structural.optimization.led.to.a.new. class.of.inhibitors:.E-.and.Z-configurated.heterocycle-methylene-substituted.indanes. and.tetralins..Here,.we.present.our.screening.system.for.the.evaluation.for.CYP11B2. inhibitors.and.summarize.extensive.structure-activity.studies.in.the.classes.of.compounds. just. mentioned.. Not. only. were. very. potent. selective. CYP11B2. inhibitors. discovered.but.selective.CYP11B1.inhibitors.and.inhibitors.of.both.enzymes.were. discovered.as.well..A.protein.model.of.CYP11B2.and.a.pharmacophore.model.of. CYP11B2.inhibitors.are.presented.as.well.as.the.experimental.validation.of.the.pharmacophore.model..The.finding.that.first.compounds.also.showed.an.inhibition.of.the. aldosterone.plasma.concentration.in vivo.is.very.important.