Synthesis and potential anti-inflammatory activity of some tetrahydrophthalazinones.
A solid-phase route for the preparation of 4a,5,8,8a-tetrahydrophthalazinon-1-ones employing the Diels-Alder reaction has been developed. Some of the new compounds have been tested for inhibition of LPS-stimulated TNF-alpha production in human whole blood from patients with chronic obstructive pulmonary disease (COPD). This evaluation revealed two compounds 17 and 18 of interest, incorporating an arylpiperazine moiety, which were found to inhibit LPS-induced TNF-alpha release like the well known anti-inflammatory PDE4 inhibitors, rolipram and roflumilast.
Gouault
Nicolas
N
Faculté de Pharmacie, 35043 Rennes-cédex, France.
Pinel
Benoit
B
Cupif
Jean-Francois
JF
Depince
Alexandra
A
Martin-Chouly
Corinne A E
CA
Belleguic
Chantal
C
David
Michele
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000631:Aminopyridines / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood*; D020889:Rolipram / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000631:Aminopyridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D003521:Cyclopropanes; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C020976:azelastine