ABSTRACT
Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.
Subject(s)
Brain Diseases/drug therapy , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Design , Fragile X Syndrome/drug therapy , Phosphodiesterase 4 Inhibitors/chemical synthesis , Allosteric Regulation/drug effects , Animals , Behavior, Animal/drug effects , Brain Diseases/enzymology , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Fragile X Syndrome/enzymology , Humans , Inhibitory Concentration 50 , Male , Mice, Inbred ICR , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck's effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
Subject(s)
Dopamine Uptake Inhibitors/chemistry , Tetrahydroisoquinolines/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/metabolism , Kinetics , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/metabolismABSTRACT
Oxindole (2) is a potent and selective PDE2 inhibitor with a favorable ADME, physiochemical and pharmacokinetic profile to allow for use as a chemical tool in elucidating the physiological role of PDE2.
