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 hav e potent phosphodiesterase (PDE) inhibition properties with high selectivit y toward PDE4. We compared the effects of various compounds derived from 9- benzyladenine with those of the selective PDE4 inhibitor RP 73401 on the in hibition of PDE4 isolated from bovine aorta, arachidonic acid, and tumor ne crosis 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) we re further investigated in vivo. Both PDE inhibitors dose dependently (1, 1 0, and 30 mg/kg per os) inhibited the recruitment of neutrophils in the bro nchoalveolar lavage fluid of mice exposed to endotoxin via aerosol. Signifi cant differences were observed with 10 and 30 mg/kg RP 73401 and 30 mg/kg N CS 613. In rats, RP 73401, but not NCS 613, significantly increased basal a cid secretion at 30 mg/kg i.v. and pentagastrin-stimulated acid secretion a t 0.3, 1, and 10 mg/kg. These results demonstrate that the compounds derive d 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 gastro intestinal side effects than second-generation PDE4 inhibitors, such as RP 73401.