Anti-inflammatory activities of a new series of selective phosphodiesterase 4 inhibitors derived from 9-benzyladenine.
Adenine derivatives substituted in position 9 have been demonstrated to have potent phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE4. We compared the effects of various compounds derived from 9-benzyladenine with those of the selective PDE4 inhibitor RP 73401 on the inhibition of PDE4 isolated from bovine aorta, arachidonic acid, and tumor necrosis factor-alpha release by mononuclear cells from healthy subjects. The rank order of potency of the various compounds for in vitro activities on arachidonic acid release is RP 73401 > NCS 613 > NCS 630 > NCS 632 > BWA 78U = NCS 631. The most effective compounds in vitro (RP 73401 and NCS 613) were further investigated in vivo. Both PDE inhibitors dose dependently (1, 10, and 30 mg/kg per os) inhibited the recruitment of neutrophils in the bronchoalveolar lavage fluid of mice exposed to endotoxin via aerosol. Significant differences were observed with 10 and 30 mg/kg RP 73401 and 30 mg/kg NCS 613. In rats, RP 73401, but not NCS 613, significantly increased basal acid secretion at 30 mg/kg i.v. and pentagastrin-stimulated acid secretion at 0.3, 1, and 10 mg/kg. These results demonstrate that the compounds derived from 9-benzyladenine, namely NCS 613, elicit anti-inflammatory activities. It is also suggested that their activities have been mediated through the inhibition of PDE4 isoenzyme. The fact that NCS 613 did not stimulate the gastric acid secretion suggests that this compound may produce fewer gastrointestinal side effects than second-generation PDE4 inhibitors, such as RP 73401.
Boichot
E
E
Institut National de la Santé et de la Recherche Médicale U456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Rennes, France.
Wallace
J L
JL
Germain
N
N
Corbel
M
M
Lugnier
C
C
Lagente
V
V
Bourguignon
J J
JJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism*; D001549:Benzamides; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002417:Cattle; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D051379:Mice; D010418:Pentagastrin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D001549:Benzamides; D004731:Endotoxins; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; C055872:9-benzyladenine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010418:Pentagastrin; D000225:Adenine; C087566:piclamilast