Quinazolines: combined type 3 and 4 phosphodiesterase inhibitors. 1998

B Charpiot, and J Brun, and I Donze, and R Naef, and M Stefani, and T Mueller
Research, Novartis Pharma AG, Basle, Switzerland. brigitte.charpiot@pharma.novartis.com

A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3/4 inhibitors and are expected to have a therapeutic potential.

UI MeSH Term Description Entries
D010726 Phosphodiesterase Inhibitors Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. Phosphodiesterase Antagonists,Phosphodiesterase Inhibitor,Phosphoric Diester Hydrolase Inhibitors,Antiphosphodiesterases,Inhibitor, Phosphodiesterase
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015105 3',5'-Cyclic-AMP Phosphodiesterases Enzymes that catalyze the hydrolysis of CYCLIC AMP to form adenosine 5'-phosphate. The enzymes are widely distributed in animal tissue and control the level of intracellular cyclic AMP. Many specific enzymes classified under this heading demonstrate additional spcificity for 3',5'-cyclic IMP and CYCLIC GMP. 3',5'-Cyclic AMP 5'-Nucleotidohydrolase,3',5'-Cyclic-Nucleotide Phosphodiesterase,CAMP Phosphodiesterase,3',5' Cyclic AMP Phosphodiesterase,3',5'-Cyclic AMP Phosphodiesterase,3',5'-Cyclic Nucleotide Phosphodiesterase,3',5'-Cyclic-AMP Phosphodiesterase,3',5'-Nucleotide Phosphodiesterase,3,5-Cyclic AMP 5-Nucleotidohydrolase,3,5-Cyclic AMP Phosphodiesterase,3',5' Cyclic AMP 5' Nucleotidohydrolase,3',5' Cyclic AMP Phosphodiesterases,3',5' Cyclic Nucleotide Phosphodiesterase,3',5' Nucleotide Phosphodiesterase,3,5 Cyclic AMP 5 Nucleotidohydrolase,3,5 Cyclic AMP Phosphodiesterase,5'-Nucleotidohydrolase, 3',5'-Cyclic AMP,5-Nucleotidohydrolase, 3,5-Cyclic AMP,AMP 5'-Nucleotidohydrolase, 3',5'-Cyclic,AMP 5-Nucleotidohydrolase, 3,5-Cyclic,AMP Phosphodiesterase, 3',5'-Cyclic,AMP Phosphodiesterase, 3,5-Cyclic,Nucleotide Phosphodiesterase, 3',5'-Cyclic,Phosphodiesterase, 3',5'-Cyclic AMP,Phosphodiesterase, 3',5'-Cyclic Nucleotide,Phosphodiesterase, 3',5'-Cyclic-AMP,Phosphodiesterase, 3',5'-Cyclic-Nucleotide,Phosphodiesterase, 3',5'-Nucleotide,Phosphodiesterase, 3,5-Cyclic AMP,Phosphodiesterase, CAMP,Phosphodiesterases, 3',5'-Cyclic-AMP
D054684 Cyclic Nucleotide Phosphodiesterases, Type 3 A cyclic nucleotide phosphodiesterase subfamily that is inhibited by the binding of CYCLIC GMP to an allosteric domain found on the enzyme and through phosphorylation by regulatory kinases such as PROTEIN KINASE A and PROTEIN KINASE B. The two members of this family are referred to as type 3A, and type 3B, and are each product of a distinct gene. In addition multiple enzyme variants of each subtype can be produced due to multiple alternative mRNA splicing. Cyclic Nucleotide Phosphodiesterase PDE3 Family,Cyclic Nucleotide Phosphodiesterases, Type 3A,Cyclic Nucleotide Phosphodiesterases, Type 3B,Phosphodiesterase 3A,Phosphodiesterase 3B,Phosphodiesterase III,cGMP-Inhibited Cyclic Nucleotide Phosphodiesterase,cGMP-Inhibited Phosphodiesterase,Phosphodiesterase, cGMP-Inhibited,cGMP Inhibited Cyclic Nucleotide Phosphodiesterase,cGMP Inhibited Phosphodiesterase
D054703 Cyclic Nucleotide Phosphodiesterases, Type 4 A cyclic nucleotide phosphodiesterase subfamily that is found predominantly in inflammatory cells and may play a role in the regulation of CELL-MEDIATED IMMUNITY. The enzyme family includes over twenty different variants that occur due to multiple ALTERNATIVE SPLICING of the mRNA of at least four different genes. Cyclic Nucleotide Phosphodiesterase PDE4 Family,Cyclic Nucleotide Phosphodiesterases, Type 4A,Cyclic Nucleotide Phosphodiesterases, Type 4A5,Cyclic Nucleotide Phosphodiesterases, Type 4B,Cyclic Nucleotide Phosphodiesterases, Type 4C,Cyclic Nucleotide Phosphodiesterases, Type 4D,Cyclic Nucleotide Phosphodiesterases, Type 4D3,PDE4 Phosphodiesterases,PDE4D3 Phosphodiesterase,Phosphodiesterase 4,Phosphodiesterase 4A,Phosphodiesterase 4B,Phosphodiesterase 4C,Phosphodiesterase 4D,Phosphodiesterase IV,Phosphodiesterase-4,Type 4 Cyclic Nucleotide Phosphodiesterase,cAMP-Specific Phosphodiesterase 4A5,Phosphodiesterase 4A5, cAMP-Specific,Phosphodiesterase, PDE4D3,Phosphodiesterases, PDE4,cAMP Specific Phosphodiesterase 4A5
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory

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