Local anti-inflammatory effect and behavioral studies on new PDE4 inhibitors.
Phosphodiesterase 4 (PDE4) inhibitors are effective anti-inflammatory drugs, although some adverse effects are observed in animals and humans. These effects have forced researchers to find new PDE4 inhibitors with less adverse effects. We recently reported the synthesis of novel heterocyclic-fused pyridazinones that inhibit PDE4. As a first step in the study of the anti-inflammatory properties of these compounds, we studied the effects of local administration of these pyridazinone derivatives in a mouse model of acute inflammation. We found that 6-Benzyl-3-methyl-4-phenylpyrazolo[3,4-d]pyridazin-7(6H)-one (CC4), ethyl 6,7-dihydro-6-ethyl-3-methyl-7-oxo-4-phenyl-thieno[2,3-d]pyridazine-2-carboxylate (CC6) and ethyl 6,7-dihydro-6-ethyl-3-methyl-4-phenyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate (CC12) reduced the paw edema induced by zymosan in mice as rolipram (the PDE4 inhibitor prototype with anti-inflammatory activity) and indomethacin did. It is well known that rolipram locally administered induces some adverse effects such as hyperalgesia. Thus, we studied this effect after local administration of CC4, CC6 and CC12 in the formalin test. We found that CC6 induced hyperalgesic effects, whereas CC4 and CC12 did not change the nociceptive threshold. Furthermore, we found that rolipram and CC6 reduced locomotor activity, whereas CC4 and CC12 did not change locomotor performance of the mice. Since CC4 and CC12 neither affected the nociceptive threshold nor changed the locomotor performance of mice, they appear more suitable than CC6 for future studies on animals and could be developed as an anti-inflammatory drug for humans.
Department of Drug Research and Evaluation, Italian National Institute of Health, Rome, Italy. pieretti@iss.it
Stefano
S
Pieretti
Luigi
L
Dominici
Amalia
A
Di Giannuario
Nicoletta
N
Cesari
Vittorio
V
Dal Piaz
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology; D015054:Zymosan
D000893:Anti-Inflammatory Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D015054:Zymosan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram