Phosphodiesterase type IV inhibitor

R)-(-)-baclofen 58,138 and phosphodiesterase type IV inhibitor, (R)-(—)-rolipram 59,187 were efficiently prepared with an intramolecular G-H insertion being used as a key step (Equations (49) and (50)). 

Examples of more basic, but enantioselective intramolecular carbenoid C-H insertion reactions were displayed in two very similar total syntheses of the phosphodiesterase type IV inhibitor i -(-)-rolipram (179, Scheme 44) [125, 126], In 1999, Hashimoto and coworkers utilized acceptor/acceptor diazo compound 180, with the nitrogen atom protected with a p-nitrophenyl moiety, as the carbenoid precursor. After screening a number of phthalimide-based dirhodium catalysts, Rh2(5 -BPTTL)4 (30) was found to give the optimal results, providing the cyclized product in 74% yield and 88% ee. 

PHOSPHODIESTERASE TYPE IV INHIBITORS [SEDA-31, 313 SEDA-32, 321 SEDA-33, 367]... 

Anada M, Mita O, Watanabe H, Kitagaki S, Hashimoto S. Catalytic enantioselective synthesis of the phosphodiesterase type IV inhibitor (R)-(—)-rolipram via intramolecular C—H insertion process. Synlett 1999 1115-1111. 

Griswold DE, Webb EF, Breton J, White JR, Marshall PJ, Torphy TJ. Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. Inflammation 1993 17(3) 333-344. 

Inamrinone, milrinone Phosphodiesterase type 3 inhibitors decrease cAMP breakdown Vasodilators lower peripheral vascular resistance also increase cardiac contractility Acute decompensated heart failure IV only duration 3-6 h Toxicity Arrhythmias Interactions Additive with other arrhythmogenic agents... 

Bara, M., Bourtchouladze, R., Winder, D. G., Golan, H. and Kandel, E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting longterm potentiation and improves memory. Proc. Natl Acad. Sci. U.S.A. 95 15020-15025,1998. 

It is a relatively selective inhibitor of cyclic GMP, cyclic AMP-PDE (phosphodiesterase) type 111 family. It causes vasodilatation with a consequent decrease in systemic vascular resistance. It increases both the force of contraction and velocity of relaxation of cardiac muscles. It is administered IV 0.75 mg/kg/min as a bolus dose followed by 5-10 pg/kg/min IV infusion and total dose not to exceed 10 mg/kg. 

Carcillo JA, Herzer WA, Mi Z, Thomas NJ, Jackson EK Treatment with the type IV phosphodiesterase inhibitor Ro 20-1724 protects renal and mesenteric blood flow in endotoxemic rats treated with norepinephrine. J PharmacoI.Exp.Ther. 279 1197-1204,... 

Milrinone is a phosphodiesterase type III/IV inhibitor that has vasodilatory properties and increases the force of contraction and velocity of relaxation of cardiac muscle. Milrinone has not been evaluated fully in the equine clinical setting. It produces a dose-dependent increase in heart rate, cardiac output, arterial blood pressure and ejection fraction and a reduction in right atrial, pulmonary artery pressures and systemic vascular resistance in normal anesthetized horses (Muir 1995). These changes persisted for 30 min after the termination of a constant i.v. infusion of milrinone. 

Several Type IV phosphodiesterase inhibitors are currently in trials for the treatment of asthma. 

It was mentioned earlier that the expression of HIV protease within E. coli gives rise to a phenotype, hi a similar fashion, it has been observed that phosphodiesterases (PDEs) when expressed in yeast affect the cells. These enzymes function to modulate intracellular concentrations of the cyclic mononucleotides cAMP or cGMP Yeast has two endogenous genes encoding PDEs which, when deleted, lead to elevated levels of cAMP within the ceU. The consequence to the yeast of elevated cAMP is increased sensitivity to heat shock and inability to utilize acetate as sole carbon source. These yeast mutants may be complemented by the human PDE gene and the phenotype reversed (Eigure 5.5). The use of such yeast in the search for inhibitors of PDEs with utility in, for example, asthma has been proposed" and certainly works with the known type IV PDEs inhibitor, rolipram. 

The cyclopentyl group creates the maximal inductive effect for a relatively reasonable bulkiness. It is often a good filling of a hydrophobic pocket as illustrated for the cAMP phosphodiesterase inhibitor rolipram (Figure 20.15). The inhibitory activity toward type IV cAMP-phosphodieste-rase is increased 10 times when the meto-methoxy group is replaced by a mem-cyclopentyl group (rofipram)." ... 

Souness, J. E., Hassall, G. A., and Parrott, D. P. (1992). Inhibition of pig aortic smooth muscle cell DNA synthesis by selective type III and type IV cyclic AMP phosphodiesterase inhibitors. Btochem. Pharmacol. 44, 857-866. 

Fig. 8.4 Yeast-based screen for inhibitors of human phosphodiesterase IV. A phosphodiesterase (PDE)-deficient yeast (PMY) will not utilize acetate as a sole carbon source and is sensitive to heat shock (55°C). Complementation with a human type IV PDE (PMY PDE) expressed from a copper-dependent (CUP1) promoter reverses the mutant phenotype. Addition of type IV PDE inhibitor (rolipram) to the complemented yeast restores the mutant phenotype (PMY -t- PDE + rolipram).

The imidazo[l,2-a]quinoxaline derivatives are cyclic nucleotide phosphodiesterase type in (PDE-111) and type IV (PDE-IV) inhibitors with promising activity in case of 4-(methylamino)imidazo[l,2-brain uptake and high selectivity for both PDE-II and PDE-X enzymes [8b] (Fig. 2.4). 

Inhibitors of a heart-specific subtype (type III) phosphodiesterase, which are positive inotropics, may be used in the short-term treatment of severe congestive cardiac failure, e.g. amrinone, enoximone and milrinone. However, developments of oral formulations of drugs of this type have been halted by the results of the PROMISE trial (Prospective Randomised Milrinone Survival Evaluation trial) which documented a paradoxical increase in mortality in class IV heart failure patients randomised to receive milrinone. However, some benzimidazole derivatives with class III phosphodiesterase inhibitor actions seem to be beneficial in heart failure. The agent vesnarinone is an orally active compound that may act as a class III phosphodiesterase inhibitor but appears to be a vasodilator with multiple mechanisms. See HEART FAUURE TREATMENT INOTROPIC AGENTS. 

---