Phosphodiesterase IV

PEE-IV Inhibitors Selective inhibitors of phosphodiesterase IV (PDE4) are in development for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Two of them contain fluorine atoms roflumilast (preregistered) bears a difluoromethyl ether and AWD-12-281 (Phase II) has a single fluorine atom (Figure 8.51). 

FIGURE 11.2 Interactions of vanadium with the hormone-sensitive G protein modulated cAMP producing signal transduction system. Bold lines with arrows leading away from V represent stimulation, blunt-ended lines represent inhibition. V shows where vanadium interactions have geen found. Pase phosphatase, PDE(IV) phosphodiesterase (IV), PEPCK phosphoenolpyrurate carboxykinase, PKA, protein kinse A inactive, PKAa PKA active. This figure was adapted from [13]. 

A highly stereoselective, nickel-catalyzed P-addition of organozincates to optically pure vinylic sulfoxide (7) played a crucial role in the synthesis of the phosphodiesterase IV inhibitor L-765,527 (CDP-840) (9) (Scheme 1)." The syn-... 

Other drugs may also have an inhibitory effect on cytokine synthesis. Elevation of cyclic AMP has an inhibitory effect on ID2 release from lymphocytes in vitro (Didier et al., 1987) and this may be achieved by theophylline at high plasma concentrations. Selective phosphodiesterase inhibitors may also be effective and recently phosphodiesterase IV inhibitors have been demonstrated to inhibit the release of IL-4 and IL-5 from T lymphocytes in vitro (Essayan et al., 1993). 

Ducrot, P., Andrianjara, C.R. and Wrigglesworth, R. (2001) CoMFA and CoMSIA ID-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase. IV. 1. Comput. Aid. Mol. Des., 15, 767-785. 

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 key step in the synthesis of CDP840 ( 108), a phosphodiesterase IV (PDE IV) inhibitor for the treatment of asthma included the Liebeskind variation of the Suzuki reaction i.e., the thiopyrimidine ether 106 was cross-coupled with pyridyl-4-boronic acid to afford 107. Catalytic hydrogenation of 107 then afforded racemic 108. 

The predominant phosphodiesterase isozyme class in inflammatory cells is composed of the enzymes that belong to the phosphodiesterase IV family (Torphy and Undem 1991). This group of enzymes has a marked preference for cyclic AMP (JC = 3-10 iM) as a substrate and demonstrates httle if any catalytic activity against cyclic GMP. Furthermore, this enzymes are selectively inhibited by compounds such as rolipram and Ro 20-1724 (Torphy and Undem 1991, Giembycz 1992). 

Eosinophil infiltration in the bronchoalveolar lavage fluid in guinea pigs was induced by recombinant human IL-8 (Lagente et al. 1995). Administration of the phosphodiesterase IV isoenzyme inhibitor, rolipram (5 mg/kg) or betamethasone (10 mg/kg) significantly P <0.05) reduced the IL-8-induced eosinophil infiltration in bronchoalveolar lavage fluid. Betamethasone may act directly on eosinophils to inhibit their infiltration by IL-8. 

Dal Piaz V, Giovannoni MP, Castellana C et al (1997) Novel heteiocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors. J Med Chem 40 1417-1421... 

Even selective monocarbonylationof2,5-dichloropyridineinthe C-2 position could be achieved by the use of the Pd(OAc)2/dppf catalyst and by limiting the amount of the EtsN base to 1.01 equiv. to prevent overcarbonylation during the synthesis of a chloropyridine N-oxide building block of a potent phosphodiesterase IV inhibitor [81]. 

Choi W-B, Churchill DRH, Lynch EJ, Reider JP, Wolante PR, inventors Merck Co., Inc., assignee. Method of preparing phosphodiesterase IV inhibitors. EP 0912517 Bl. 

---