CAMP phosphodiesterase inhibitors

Martin prepared 5-trimethylstannylindole and effected coupling with bromobenzene to give 5-phenylindole [125], In a search for new cAMP phosphodiesterase inhibitors, Pearce prepared the furylindole 190 from 5-bromoindole and 5-ferr-butoxy-2-trimethylstannylfuran [196a], Benhida and co-workers explored Stille couplings of 6-bromo- and 6-iodoindole, and methyl 6-iodoindol-2-ylacetate with a variety of heteroarylstannanes and vinylstannanes [196b]. 

Horowski, R. and SastreHernandez, Y.M., Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients global evaluation of the preliminary reports, Curr. Ther. Res. Clin. Exp., 38, 23, 1985. 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

Griebel G, Misslin R, Vogel E, Bourguignon J (1991) Behavioral effects of rolipram and structurally related compounds in mice behavioral sedation of cAMP phosphodiesterase inhibitors. J Neurochem 58 321-323... 

Fleischhacker, W.W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R., Gerlach, W., Jaklitsch, H., Sastre-y-Hernandez, M., Schmedlng-Wlegel, H., Sperner-Unterweger, B., Voet, B., and Schubert, H. (1992) A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 26 59-64. 

Phosphodiesterases are a group of enzymes that, among other actions, hydrolyse cAMP. Phosphodiesterase inhibitors are selective for phosphodiesterase III (PDE-III) isoenzyme present in the heart. They prevent the degradation of cAMP, thereby increasing its intracellular concentration (Figure 8.4). This leads to an increase in the intracellular concentration of Ca2+ and an increased contractility and heart rate. PDE-III inhibitors have no adrenoceptor agonistic activity and therefore can be used in combination with other sympathomimetic drugs. They also increase cAMP levels in vascular smooth muscle, but this results in lower intracellular Ca2+ concentrations and thus vasodilatation. 

Lam, S.C.T. Packham, M.A. Isolation and kinetic studies of nucleoside diphosphokinase from human platelets and effects of cAMP phosphodiesterase inhibitors. Biochem. Pharmacol., 35, 4449-4455 (1986)... 

Lam SC-T Guccione MA, Packham MA, et al. Effect of cAMP phosphodiesterase inhibitors on ADP-induced shape change, cAMP and nucleoside diphosphokine activity of rabbit platelets. Thromb Haemost 1982 47 90-95. 

Benzylisoquinolines (IQ,-CH2-Phe) Ethaverine and laudanosine (L-type Ca2+ channel blockers from opium) papaverine (cAMP phosphodiesterase inhibitor and smooth muscle relaxant derived from opium and Rauwolfia serpentina (Apocynaceae)) protopine (MD-Phe C9N Phe-MD) opium-derived smooth muscle relaxant) (+)-reticuline (opium-derived adrenergic receptor ligand and hair growth accelerant). 

Simple lignans involving a Phe-C -C -Phe structure are illustrated by the antioxidant and Ca2+ channel blocker nordihydroguaiaretic acid (NDGA) (3,4-dihydroxyphenyl-CH2-CH(CH3)-CH(CH3)-CH2-(3, 4 -dihydroxyphenyl)), the bitter-tasting phyllanthin and the cAMP phosphodiesterase inhibitor ar-hinokiresinol. Simple lignans of the C3—Phe—Phe—C3 kind are illustrated by the antibacterials honokiol and the protein kinase inhibitor magnolol. 

Simple chromones (Phe ] y-pyran-4-one) include the glucoside biflorin (a cAMP phosphodiesterase inhibitor and free radical scavenger) and the 2-phenoxychromone capillarisin (an aldose reductase inhibitor) as well as a number of variously cytotoxic and antimicrobial compounds. 

Furanochromones (furan [ Phe y-pyran-4-one) have a furan ring fused with the benzene moiety of the chromone. Khellin, the related khellol glucoside and visnagin (dehydrokhellin) derive from seeds of Ammi visnaga (Apiaceae), both khellin and visnagin being phototoxic and vasorelaxant cAMP phosphodiesterase inhibitors. 

II, two 3, 5 -cAMP phosphodiesterase inhibitors (87JA2717). If these transformations are employed twice, the inverse electron-demand cycloaddition reactions represent a valuable synthetic strategy for the following conversions 1,2,4,5-tetrazine - pyridazine - benzene (or in-doline). 

Dawicki, DD, Aganval, KC, Parks, RE, Jr, Potentiation ofthe antiplatelet action of adenosine in whole blood by dipyridamole or dilazep and the cAMP phosphodiesterase inhibitor, RA-233, Thromb. Res, 1986,43 161-175. 

Rhoden, K.J. and Barnes, P.J. (1990). Potentiation of nonadrenetgic neural relaxation in guinea pig airways by a cyclic cAMP phosphodiesterase inhibitor. J. Pharmacol. Exp. Ther. 252, 396-402. 

The cyclopentyl group creates the maximal inductive effect for a relatively reasonable bulkiness. It is often a good filling of a hydrophobic pocket as illustrated for the cAMP phosphodiesterase inhibitor rolipram (Figure 20.15). The inhibitory activity toward type IV cAMP-phosphodieste-rase is increased 10 times when the meto-methoxy group is replaced by a mem-cyclopentyl group (rofipram)." ... 

Forskolin, or other elevators of intracellular cAMP such as rolipram (a cAMP phosphodiesterase inhibitor) can induce PP2A activation [111, 143, 144]. Although most of their cellular effects depend on augmented PKA and adenylate cyclase activities, the mechanism by which forskolin activates PP2A does not require an increase in PKA activity [ 143]. This is best proven by the persisting PP2A stimulatory effect of 1,9-dideoxy-forskolin [ 111 ], a forskolin derivative that does not result in adenylate cyclase activation and increased cAMP production. In cellular [111, 113, 144] and in vivo [111] models of CLL, CML, and AML, rolipram, forskolin. 

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... 

Inhibitors of cAMP phosphodiesterase Inhibitors of fungal enzymes Inhibitors of mitochondrial respiration Inhibitors of oxidases Enzymes... 

Bourguignon J, Desaubry L, Raboisson P, Wermuth CG, Lugnier C (1997) 9-Benzyladenines potent and selective cAMP phosphodiesterase inhibitors. J Med Chem 40 1768-1770... 

---