Phosphodiesterase PDE

Contraindications Renal impairment coronary or cerebral arteriosclerosis concurrent use with phosphodiesterase-5 (PDE-5) inhibitors including sildenafil (>25 mg), tadalafil, or vardenafil hypersensitivity to phentolamine or related compounds. 

The solid phase parallel synthesis of tetrahydroimidazo[l,2-a][l,3,5]triazepin-2-thiones and 2-imines has been reported starting from resin-bound peptides <06JCO127>. Pyrazolo[r,5 l,6]pyrimido[4,5-rf]pyridazinones with potent and selective phosphodiesterase 5 (PDEs) inhibitory activity have been described <06JMC5363>... 

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... 

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... 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

An entire new field of therapeutics arose with the serendipitous discovery of the effect on erectile function of sildefanil (see Chapter 15), far better known as Viagra . The enormous and still rising market opened by that drug has predictably led to the search for other inhibitors of phosphodiesterase 5, the enzyme responsible for this activity. The stmctures of many follow-on agents have hewed fairly close to the original PDE 5 inhibitor. Others, such as avanafil (58-9), differ markedly from sildefanil in structure. The synthesis of this agent in effect consists of a series of displacement reactions. Thus, reaction of the benzylamine (58-1) with chloropyrimidine... 

As long as the couple are not stressed by the sexual position they use, there is no evidence of increased cardiac stress to a man or woman. Man on top, woman on top, side to side, oral sex, and masturbation are cardiologically equivalent. In homosexual relationships, other than casual, anal intercourse is not associated with increased cardiac stress provided proper lubrication is used and amyl nitrate ( poppers ) are not used in the presence of a phosphodiesterase type-5 (PDE-5) inhibitor by the patient or partner. 

Fig. 1.15 Structure of the phosphodiesterase type 5 (PDES) inhibitor sildenafil [25,26].

The erectile dysfunction group of drugs, of which sildenafil is most common, are potent inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE-5). The other two available drugs are tadalafil (Cialis) and... 

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). ... 

Phosphodiesterase 5 (PDE5) is found in blood vessels supplying the corpora cavernosa. Sildenafil inhibits PDE 5 - T cGMP -> vasodilation - T blood flow ->T erectile response. If used concomitantly with nitrates or other potent vasodilators, the excessive fall in blood pressure may lead to death from cardiovascular causes, including myocardial infarct. 

Condensation of 2-amino-3-bromo-l,6-naphthyridines 81 with potassium O-ethyl xanthate in A-methylpyrrolidone afforded thiazolo[4,5-6][l,6]naphthyridine-2(3//)-thiones 303 whose subsequent methylation and hydrolysis in the presence of sodium methoxide afforded thiazolonaphthyridones 304 inhibiting adenosine-3, 5 -cyclo-phosphate phosphodiesterase (cAMP PDE III) (1995JMC2546). 

Figure 32.2 Inhibitory effects of XI on human thyroid signaling intracellular cascades. R, receptor ATP, adenosine triphosphate nucleotide PuR, purinergic receptor Gs, stimulatory G protein of adenylyl cyclase Gi, inhibitory G protein of adenylyl cyclase Gq, stimulatory G protein of phospholipase C AC, adenylyl cyclase PLC, phospholipase C IPS, inositol 1,4,5-trisphosphate DAG, diacylglycerol PKC, protein kinase C DUOX, dual oxidase PGE, prostaglandin E1 TSHR, TSH receptor cAMP, cyclic 3 -5 adenosine monophosphate PDE, cAMP phosphodiesterase 5 AMP, adenosine monophosphonucleotide cA PK, cAMP-dependent protein kinase FK, forskolin ------> Stimulation inhibition — generation.

C. Degradation Stimulation and inhibition of cyclic nucleotide degradation (Sites 5 and 6) are very important mechanisms for controlling their intracellular levels, and to date represent the most fertile sources of prototype drugs. The variety of structures that can influence the activity of the phosphodiesterase enzymes (PDE s) and the importance of these enzymes in drug development have been recently reviewed . Since PDE s are influenced by a number of hormones, e.g., insulin and cholecysto-kinin, it is at least theoretically possible that some drugs could block the action of these hormones on PDE s (Site 7). However, no such drug has yet been found. 

Within the last 10 years there have been a number of important developments in terms of selective PDE inhibitors with the licensing of phosphodiesterase 5 (PDE5) inhibitors in the late 1990s paving the way for a range of new clinical applications. 

Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that catalyze the hydrolysis of 3, 5 -cyclic guanosine monophosphate (cGMP) or 3, 5 -cyclic adenosine monophosphate (cAMP) to 5 -guanosine monophosphate (GMP) or 5 -adenosine monophosphate (AMP), respectively. 

Sildenafil (Viagra ), tadalafil (Cialis ), and vardenafil (Levitra ) act by selectively inhibiting phosphodiesterase (PDE) type 5, an enzyme that breaks down cGMP. By inhibiting the breakdown of cGMP, smooth muscle relaxation is... 

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