PDEs inhibitors

Only those indoles that are sufficiently basic to be protonated by acetic acid are reduced under these conditions. Thus, 5-nitroindole and 2,3-diphenylindole are recovered unchanged,whereas 5,6-dimeth-oxyindole is cleanly reduced to 5,6-dimethoxyindoline in 86% yield with NaBHsCN/HOAc. " This differential reactivity has been exploited by Cava and Rawal in their synthesis of CC-1065 analogs in which only the more basic double bond in (23) is reduced (equation 61).Indeed, this same tactic has since been utilized by Boger," Moodyand Sundberg, and their coworkers, in their respective synthetic efforts towards CC-1065 and the related phosphodiesterase inhibitors PDE-I and PDE-II. Likewise, Joule and coworkers have utilized NaBHsCN/HOAc in a chemoselective reduction of the more basic indole double bond in benzodipyrrole (24 equation 62). ... 

The synthesis of several analogs of the phosphodiesterase inhibitors PDE-I (134) and PDE-II (135) adapted the Eschenmoser reaction to perform a key cyclization that demonstrated its utility in constructing highly functionalized heterocycles. These tricyclic compounds are of additional interest because of their presence in the potent antitumor antibiotic CC-1065 (136). Cyclization of the pyrrolylthiopyrrolidi-none (137) to the tricyclic structure was achieved either by the Eschenmoser reaction or by the Knoeven-... 

The reaction is sensitive to the diene/dienophile spacer as well as subtle features apparently important for substrate/product stability under the reaction conditions (200-230°C). Table 10-IV summarizes the intramolecular Diels-Alder reactions of 1,2-diazines. These observations have found application in the total synthesis of the cAMP phosphodiesterase inhibitors PDE-I and PDE-II (24), constituting the central and right-hand segments of the potent antitumor antibiotic CC-1065 [Eq. (17)].76... 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. 

Arylimino-2,3,6,7-tetrahydro- (00MIP19) and 2-aryloxy-6,7-dihydro-4//-pyrimido[6,1-a]isoquinolin-4-ones (00MIP20) were patented as PDE inhibitors and as useful agents for treatment of respiratory disorders, respectively. 

FIGURE 9.13 Cardiovascular responses to the PDE inhibitor fenoximone in different contexts, (a) In vivo effects of fenoximone in anesthetized dogs. Ordinates reflect positive inotropy. Redrawn from [47]. (b) In vitro effects of fenoximone in guinea pig untreated isolated left atria (filled circles) and atria in the presence of sub threshold P-adrenoceptor stimulation with prenalterol (open circles). Redrawn from [48]. 

Inhaled NO has been used for treatment of persistent pulmonary hypertension of newborn infants, critical respiratory failure of preterm infants, and acute hypertension of adult cardiac surgery patients. PDE-5 inhibitors such as sildenafil are also effective for treatment of pulmonary hypertension. The combination of PDE-5 and NO inhalation yields additive beneficial effects on pulmonary hemodynamics. On the other hand, measurement of exhaled NO is a noninvasive and reproducible test that is a surrogate measure of airway inflammation in patients with bronchial asthma. 

PDE Family Genes Probable splice variants Regulatory domains/role Phosphorylation Substrate (s) Commonly used inhibitors... 

Beyond Viagra, there are a number of other PDE inhibitors that are used clinically. In fact, the classic drugs papaverine and dipyridamole were used clinically before their effects on PDEs were known. Caffeine and theophylline (a compound found in tea) are also PDE inhibitors. However, all of these drugs most likely have multiple targets, making conclusions regarding the roles of PDEs in processes that are sensitive to these agents difficult to interpret. Certainly, some of their effects are due to their actions on adenosine receptors. 

The most X-ray intensive screening method was described by Card et al. [8] on the design of phosphodiesterase (PDE) inhibitors (Figure 1.7). The authors initially biochemically screened a 20,000 member library of small molecular weight (120-350 MW) core scaffold compounds against 5-PDE isoforms at 200 pM. Multiple isoforms of PDE were used in order to eliminate the number of false positives obtained from the screen. There were 316... 

Gresser U, Gleiter CH. Erectile dysfunction comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil review of the literature. Eur J Med Res 2002 7 435-446. 

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