ABSTRACT
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Animals , Anti-Inflammatory Agents/pharmacology , Cyclic N-Oxides/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Discovery , Humans , Models, Molecular , Oxazoles/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.
Subject(s)
Oxazoles/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/drug effects , Models, Molecular , Oxazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , RatsABSTRACT
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Subject(s)
Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Neurokinin-1 Receptor Antagonists , Urea/analogs & derivatives , Urea/pharmacology , Animals , Anti-Anxiety Agents/chemical synthesis , Benzyl Alcohols/chemistry , Crystallography, X-Ray , Drug Evaluation, Preclinical , Fluorine/chemistry , Gerbillinae , Models, Molecular , Molecular Structure , Motor Activity/drug effects , Structure-Activity Relationship , Urea/chemical synthesisABSTRACT
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Subject(s)
Neurokinin-1 Receptor Antagonists , Urea/analogs & derivatives , Animals , Biological Availability , Dose-Response Relationship, Drug , Gerbillinae , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Motor Activity/drug effects , Protein Binding , Rats , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
The synthesis and binding affinity for hNK(1) and hNK(2) receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK(1) activity was shown by one enantiomer (13a) and NK(2) activity was shown by the other enantiomer (13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK(2) active piperazine (15) showed that the 2R configuration was associated with NK(2) activity. Further derivatization indicated that dual NK(1)/NK(2) activity could be built into the 2R series.
