DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITIES OF NEW THIENO[3,2-D]PYRIMIDINES AS SELECTIVE TYPE-4 PHOSPHODIESTERASE INHIBITORS

A common pharmacophore for compounds structurally related to nitraquaz one has been derived. Using this pharmacophore, new structures have be en designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodies terase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2- d]-pyrimidine (4) was selected for optimization. The effects of change s to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, se lective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [H-3]rolipram from its binding site and also to potentiate isoprenali ne-induced cAMP accumulation in isolated guinea pig eosinophils. Of th ese, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an inte resting profile, with an important improvement in PDE 4/[H-3]rolipram ratio with respect to reference drugs, and good activity in cAMP poten tiation, consistent with efficient cell penetration.