PDE4 inhibitors

Several other research teams used the Paal-Knorr condensation to prepare 2,5-disubstituted furans that were investigated as potential enzyme inhibitors. Nagai produced furan 17 via treatment of dione 16 with sulfuric acid and subsequently examined the activity of 17 toward a retenoic acid receptor. Perrier discovered that furan 19, derived from dione 18, is a potent PDE4 inhibitor and may have anti-inflammatory activity. ... 

In the aitways, inhibition of PDE4 is much more antiinflammatory than bronchodilatory. Although effective in animal experiments, the neuronal and gastric side effects of PDE4-inhibitors have so far impeded their use in humans. Two new orally active PDE4-inhibitors (roflumilast, cilomilast) have shown some effectiveness in advanced clinical trials, but have not yet been approved. 

As with pyridazines, phthalazines, the other benzopyridazines, were also prepared most frequently through the condensation of hydrazines with carbonyl-containing compounds, typically phthalate derivatives. Recently, Napoletano and co-workers demonstrated the condensation of hydroxylactone 189 and hydrazine to afford phthalazones 190. After POCI3 chlorination, advanced intermediates for a novel series of PDE4 inhibitor I, phthalazines 191 were prepared <00BMC2235>. 

The rationale for the use of PDE4 inhibitors for the treatment of depression comes from the observations that... 

PDE4 (Table 1, entry 10) A library of about 20,000 "scaffold" compounds with molecular weights of 125-350 Da were screened in a combination of biochemical assays and crystallography studies to identify the PDE4 inhibitor pyrazole ester derivative 38 [45]. A 4000-fold increase in potency was achieved after only two rounds of chemical synthesis to give 39. 

T. R., LalibertO, F., Lynch, J.J., Mancini, J., Martins, E., Masson, P., Muise, E., Pon, D. J., Siegl, P.KS., Styhler, A., Tsou, N.N., Turner, M.J., Young, R.N. and Girard, Y. (2003) Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium... 

PDE4 Inhibitor Acute (central nervous system) Emesis Rolipram24-25... 

Another recent example of the apphcation of these catalyst systems is the efficient synthesis of the chiral alcohol (J) in a route to L-869,298, a potent PDE4 inhibitor, by O Shea et alP at Merck Frost, as shown in Figure 1.24. 

To reduce toxicity while maintaining therapeutic efficacy, more selective inhibitors of different isoforms of PDE4 were developed (eg, roflumilast, cilomilast, and tofimilast), particularly for the treatment of chronic obstructive pulmonary disease (COPD), but they were abandoned after clinical trials showed that their toxicities of nausea, headache, and diarrhea restricted dosing to subtherapeutic levels. A new generation of selective PDE4 inhibitors is now under development, but none seems close to approval for clinical use. 

Spina D PDE4 inhibitors Current status. Br J Pharmacol 2008 155 308. [PMID 18660825]... 

Timmer W, Leclerc V, Birraux G, et al.The new PDE4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol 2002 42(3) 297-303. 

The most prominent group of structurally related PDE4 inhibitors was built on the structure of the archetypical inhibitor rolipram (53). Rolipram also serves to illustrate a particular difficulty in the field of PDE4 inhibitors, namely, the confusion that has surrounded the different behaviors of PDE4 preparations toward this (and other) inhibitors. This has led to the concept of low-affinity rolipram binding (LARB,... 

The defining structural element found in rolipram and its relatives is the dialkoxyphenyl (catechol) moiety. Although the development of rolipram (then for depression) was terminated early, many companies have since disclosed PDE4 inhibitors intended primarily for indications such as asthma and COPD (chronic obstructive pulmonary disease) [58], For a long time, cilomilast (Ariflo, 54) has appeared to be ahead in this race [59], In November 2003, GSK received an approvable letter from the FDA, despite the FDA advisory panel s earlier negative opinion of the compound. The extent to which new studies may have been requested by the FDA and will delay approval remains to be seen. 

Figure 9.21 Aryl substituted heterocyclic compounds as PDE4 inhibitors.

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