Novel Heterocyclic-Fused Pyridazinones as Potent and Selective Phosphodiesterase IV Inhibitors

Abstract

A series of 6-aryl-4,5-heterocyclic-fused pyridazinones were designed and synthesized as selective phosphodiesterase (PDE) IV inhibitors. Biological evaluation of these compounds demonstrated a good selectivity profile toward the PDE IV family and greatly attenuated affinity for the Rolipram high-affinity binding site that seems to be responsible for undesiderable side effects. Structure-activity relationships (SARs) studies showed that the presence of an ethyl group at pyridazine N-2 is associated with the best potency and selectivity profile.

Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity for the high-affinity rolipram binding site

“…CC3 displayed 35% inhibition vs. PDE3 at 20 µM concentration and an IC 50 of 2 µM for PDE4 (Dal Piaz et al 1997). From these data it can be seen that up to concentrations of 10 µM all these inhibitors will block predominantly one of the isoenzymes, that is PDE3 in the case of motapizone and PDE4 in the case of rolipram and CC3.…”

“…Compound pyridazin-7(6H)-one; Fig. 1) was synthesized in the laboratory of Dipartimento di Scienze Farmaceutiche (Università di Firenze, Italy) following the procedure described by Dal Piaz et al (1997). Rolipram was a gift from Schering (Berlin, Germany) and motapizone was from Nattermann-Rhone Poulenc-Rorer (Cologne, Germany).…”

“…Monocytes and lymphocytes were separated by counterflow centrifugation using the JE-6B-elutriator system (Beckman Instruments, Palo Alto, Calif., USA) as described by Grage-Griebenow et al (1993). The resulting monocyte fraction consisted of more than 95% pure monocytes as determined by FACS analysis of the cells' light scatter pattern as well Uhlig et al (1997), Schudt (2001) andDal Piaz et al (1997), respectively as of their CD14-antibody staining. Cells were resuspended in RPMI 1640 medium (containing 100 U/ml penicillin and 100 µg/ ml streptomycin) in a concentration of 1×10 6 cells/ml.…”

“…We recently have synthesized PDE4 inhibitors such as CC3 (Dal Piaz et al 1997) that in comparison with rolipram bind with much reduced affinity to the HARBS. The ratio between PDE4 inhibitory activity and affinity for HARBS is 2.0 for CC3 and 53.3 for rolipram (Dal Piaz et al 1997).…”

“…The ratio between PDE4 inhibitory activity and affinity for HARBS is 2.0 for CC3 and 53.3 for rolipram (Dal Piaz et al 1997). The chemical structure of CC3 is depicted in Fig.…”