ABSTRACT
A series of (4-substituted prolyl)prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Among those tested, the 4beta-[4-(hydroxyphenyl)prolyl]prolinenitriles showed a potent inhibitory activity with a long duration of action. Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. The activity profiles of the synthesized compounds are reported and structure-activity relationships are also presented.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Animals , Area Under Curve , Biological Availability , Chromatography, Thin Layer , Drug Design , Drug Stability , Glucuronidase/chemistry , Humans , In Vitro Techniques , Indicators and Reagents , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Solutions , Spectrometry, Mass, Fast Atom Bombardment , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spectroscopy, Fourier Transform Infrared , Structure-Activity RelationshipABSTRACT
The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Acetates/chemistry , Administration, Oral , Animals , Chelating Agents/chemical synthesis , Chelating Agents/therapeutic use , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclohexanecarboxylic Acids/chemistry , Humans , Hydroxamic Acids/chemistry , Isomerism , Nitriles , Phosphodiesterase Inhibitors/pharmacology , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies. More detailed biological evaluations of selected compounds are also presented.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Animals , Binding Sites , Bronchoconstriction/drug effects , Computer Simulation , Cyclic Nucleotide Phosphodiesterases, Type 4 , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Ferrets , Gastric Emptying/drug effects , Guinea Pigs , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Male , Rats , Rats, Sprague-Dawley , Rolipram/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Vomiting/drug therapyABSTRACT
A series of 4-anilinopyrazolopyridine derivatives were synthesized and biologically evaluated as inhibitors of phosphodiesterase (PDE4). Chemical modification of 3, a structurally new chemical lead that was found in our in-house library, was focused on 1- and 3-substituents. Full details of the discovery of a new orally active chemical lead 5 are presented. Structure-activity relationship data, pharmacological evaluation, and the subtype selectivity study are also presented.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Animals , Bronchoconstriction/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Ferrets , Gastric Emptying/drug effects , Guinea Pigs , Humans , Lipopolysaccharides/antagonists & inhibitors , Male , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , SRS-A/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , Vomiting/chemically inducedABSTRACT
The design, synthesis, and biological evaluation of a series of pyrazolopyridines was carried out. Structural optimization of the aniline moiety of 4-anilinopyrazolopyridine derivative 3a, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was performed successfully. The details of the discovery of new orally active PDE4 inhibitors, which are expected to show therapeutic potential, are presented and their structure-activity relationships are discussed. Pharmacological evaluation and pharmacokinetic data for representative compounds are also presented.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Pyridines/administration & dosage , Pyridines/therapeutic use , Aniline Compounds/chemistry , Animals , Biological Assay , Cyclic Nucleotide Phosphodiesterases, Type 4 , Drug Design , Ferrets , Guinea Pigs , Humans , Male , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , U937 CellsABSTRACT
Based on the promising results obtained by the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (the carboxylic acid moiety, nitrile moiety and 3-cyclopentyloxy-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3 ?3 ?0]octane template with more stereochemical diversity than the cyclohexane template of Ariflo 1. Biological evaluation of the decyanated analogs and further optimization of the cyclopentyloxy moiety of 2a-b were also performed. Among the compounds tested, 2a, 7a-b and 12a were found to be orally active and were estimated to have therapeutic potential based on cross-species and same-species comparisons. The structure-activity relationships (SARs) of these compounds were investigated and pharmacokinetic data for 2a and 7b were also obtained by single-dose studies in rats.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Bronchoconstriction/drug effects , Bronchoconstriction/physiology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Ferrets , Gastric Emptying/drug effects , Guinea Pigs , Humans , Lipopolysaccharides/pharmacology , Male , Phosphodiesterase Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism , U937 CellsABSTRACT
Based on the successful results in the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (carboxylic acid moiety, nitrile moiety and 3-cyclopentyl-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3.3.0]octane template instead of a cyclohexane template. As a result, 2a, 7a and 7b were found to be orally active and were predicted to have an improved therapeutic potential based on evaluation by cross-species and same-species comparisons. Structure-activity relationships (SARs) of these compounds are also discussed.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/therapeutic use , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Bronchoconstriction/drug effects , Bronchoconstriction/physiology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Humans , Phosphodiesterase Inhibitors/administration & dosage , Rats , U937 CellsABSTRACT
Structural optimization of pyrazolopyridine derivative 2, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was carried out successfully. The process of discovery of new orally active PDE4 inhibitors, which are expected to possess therapeutic potential, is presented and their structure-activity relationships are discussed.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Bronchoconstriction/drug effects , Bronchoconstriction/physiology , Bronchoconstrictor Agents/administration & dosage , Bronchoconstrictor Agents/therapeutic use , Cyclic Nucleotide Phosphodiesterases, Type 4 , Ferrets , Gastric Emptying/drug effects , Guinea Pigs , Humans , Phosphodiesterase Inhibitors/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Pyridines/administration & dosage , Pyridines/chemistry , Pyridines/therapeutic use , Rats , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Vomiting/chemically inducedABSTRACT
Based on the hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system (CNS), design and synthesis of a hydrophilic analogue is considered to be one approach to improving the side-effect profile of Ariflo 1. Water-soluble piperidine derivatives were found to possess therapeutic potential.