Francesco Marchini

The synthesis and biological evaluation of a novel series of phthalazine PDE4 inhibitors I

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.

Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 μg kg−1 min−1 intravenously) decreased arterial blood pressure (by 11±3%; P<0.05) and increased coronary blood flow (by 12±4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2±0.1 c.p. 10.7±3.3; P<0.05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia‐reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST‐segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg−1, i.v.) a selective antagonist of bradykinin at B2 receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin.

Phthalazine PDE4 inhibitors. Part 3: the synthesis and in vitro evaluation of derivatives with a hydrogen bond acceptor.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.

Z1046, a novel peripheral dopaminergic agent

Abstract The D1-like, D2-like, α1 and α2 in vitro activities of 2-aminotetraline congeners are reported. Z1046 was selected and the antihypertensive activity in rat and dog was evaluated both by intravenous and oral routes.

Pharmacological evidence for the presence of a peripheral postjunctional D2-like dopamine receptor in rabbit splenic artery

This study was designed to investigate the involvement of postjunctional D2‐like receptors in a rabbit vasculature model used to evaluate the D1‐like agonist activity. Dopamine, epinine and (−)‐DP‐5,6‐ADTN, three mixed D1/D2‐like agonists, fenoldopam and SKF 82958, two selective D1‐like agonists and SKF 89124, a selective D2‐like agonist, were administered cumulatively in precontracted and α/β‐blocked rabbit splenic artery rings in order to evaluate their D1‐like‐mediated vasorelaxant activity before and after pretreatment with the selective D2‐like antagonist YM 09151‐2 (1 nM). Dopamine (pD2=6.35±0.09), epinine (pD2=6.73±0.13), (−)‐DP‐5,6‐ADTN (pD2=7.56±0.09) and SKF 82958 (pD2=8.55±0.10) reversed completely the U46619‐induced contracture whereas SKF 89124 was inactive up to 10 μM and fenoldopam acted like a partial agonist (pD2=8.31±0.09, α=0.62). The selective D2‐like dopamine receptor antagonist YM 09151‐2 (1 nM) significantly (P<0.05) potentiated the vasorelaxant activity of dopamine (pD2=7.01±0.07), epinine (pD2=7.14±0.08), (−)‐DP‐5,6‐ADTN (pD2=8.19±0.09) and SKF 89124 (40% relaxation at 10 μM), whereas it did not alter the effects of fenoldopam (pD2=8.40±0.09, α=0.68) and SKF 82958 (pD2=8.58±0.08). The D2‐like antagonist YM 09151‐2 induced the same degree of effect with all the substances tested in both endothelium‐denuded and endothelium‐intact preparations. The selective D2‐like dopamine receptor agonist SKF 89124 did not produce any intrinsic effect on the splenic artery, but was able to produce a rightward shift of the forskolin‐induced relaxation. The results of these experiments support the existence of a non‐endothelial postjunctional D2‐like dopamine receptor counteracting the D1‐like‐mediated vasodilatation in rabbit splenic artery, probably by the inhibition of adenylate cyclase.