Phosphodiesterases analogs

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

FIGURE 21-2 Chemical pathways for the synthesis and degradation of cAMP. cAMP is synthesized from ATP by the enzyme adenylyl cyclase with the release of pyrophosphate, and is hydrolyzed into 5 -AMP by the enzyme phosphodiesterase. Both reactions require Mg2. Analogous reactions underlie the synthesis and degradation of cGMP (not shown). PP, inorganic pyrophosphate. 

But now, a strategy, used for the synthesis of derivative (622) (lit. synthesis (622) see in Ref. 555), which is the most efficient analog of the commercial drug rolipram with a broad spectrum of action (in particular, anti-inflammatory, antidepressant, neuroprotective, and immunodepressing effects), is presented in Scheme 3.286. (The principle action of rolipram is based on selective inhibition of adenosine monophosphate (AMP)-specific phosphodiesterase.) Derivative (622) is almost 10 times more efficient than rolipram, but the biological activity of (622) was determined only for the racemate (555). 

This enzyme [EC 3.1.4.39], also known as alkylglycero-phosphoethanolamine phosphodiesterase, catalyzes the hydrolysis of l-alkyl-sn-glycero-3-phosphoethanolamine to produce 1-alkyl-xn-glycerol 3-phosphate and ethanol-amine. The enzyme will also act on the acyl and choline analogs of the lipid. 

Another group of thalidomide analogs, selective cytokine inhibitory drugs (SelCIDs), are phosphodiesterase type 4 inhibitors with potent anti-TNF-a activity but no T-cell co-stimulatory activity. Several SelCIDs are currently under investigation for clinical use. 

Attachment of phosphopantetheine to proteins is catalyzed by a phosphotransferase that utilizes CoA as the donor. A phosphodiesterase removes the phosphopantetheine, providing a turnover cycle.15, 5b A variety of synthetic analogs have been made.4 16 The reactive center of CoA and phosphopantetheine is the SH group, which is carried on a flexible arm that consists in part of the (3-alanine portion of pantothenic acid. A mystery is why pantoic acid, a small odd-shaped molecule that the human body cannot make, is so essential for life. The hydroxyl group is a potential reactive site and the two methyl groups may enter into formation of a "trialkyl lock" (p. 485), part of a sophisticated "elbow" or shoulder for the SH-bearing arm. 

This synthetic procedure was used to synthesize thiophene analogs of PDE-I and PDE-II such as 196, compounds able to inhibit cyclic adenosine-3, 5 -monophosphate phosphodiesterase (86JCS(CC)826). In this case, the photochemical reaction by using Pd on carbon methodology gave the product in 64% yield. 

The addition of phosphodiesterase inhibitors such as isobutylmethylxanthine (IBMX) and cyclic AMP analogs such as the 8-bromo- and dibutyryl-derivatives resulted in a stimulation of synthesis which could not be blocked by the co-addition of opiates. This implies that opiates are exerting their effect at the level of adenylate cyclase activation. The actual effect of these drugs on cellular cyclic AMP levels was determined by radioimmunoassay as shown in Table III. 

PGR analog/mimetic (epoprostenol, FR181157) Sildenafil Inhibits platelet aggregation Inhibits type-5 phosphodiesterase and reduces platelet activation... 

The reaction mixture contained cyclic formycin monophosphate, an analog of cAMP, as the substrate, Tris-HCl (pH 7.5) as buffer, and MgQ2. The reaction was started by the addition of the enzyme. Samples were removed at intervals and injected directly onto the reversed-phase column for analysis. Figure 9.108 shows chromatograms after 10 and 30 minutes of incubation. While the amount of cFoMP substrate in the incubation mixture has declined and the amount of product FoMP has increased, the amount of formycin A (FoA), the analog of adenosine, has remained unchanged. When the area of each peak is plotted as a function of reaction time, the data shown in the central inset are obtained. Although these data clearly illustrate the activity of the cyclic phosphodiesterase, they also show the absence of any 5 -nucleotidase. 

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