Imidazole derivatives as inhibitors of cyclic nucleotide phosphodiesterases

Inhibition of separated forms of phosphodiesterases from pig coronary arteries by uracils and by 7-substituted derivatives of 1-methyl-3-isobutylxanthine

“…Compound 4b (10 4 M), which resembles 7-Bzl-MIX more closely than any of the other uracils studied, inhibited hydrolysis of 1 µ cAMP and cGMP by peak I by 37 and 30%, respectively, and inhibited hydrolysis of 1 µ cAMP by peak II by only 9%. These data, along with similar findings for various imidazole derivatives, 19•29 indicate that the intact xanthine nucleus or at least a larger heterocyclic ring system than uracil or imidazole is necessary to effectively compete with the cyclic nucleotides for the hydrolytic site of phosphodiesterase. MIX (1) is one of the most potent inhibitors of cyclic nucleotide phosphodiesterase that has been reported; it is 30-60 times more potent than theophylline as an inhibitor of pig coronary artery phosphodiesterases when either cAMP or cGMP is used as substrate.1 Similar differences in potency have been reported for MIX and theophylline as inhibitors of cAMP phosphodiesterase activities from other tissues.12-14 MIX has also been shown to be relatively selective for peak I phosphodiesterase with either cyclic nucleotide as substrate.1 Various 7-substituted MIX derivatives (Table II, [5][6][7][8][9][10][11][12][13][14][15][16][17] were prepared in an attempt to determine if these substituents would increase the inhibitory potency and/or selectivity of the MIX molecule.…”

“…arteries. 19 We have, therefore, prepared and studied a series of 7-substituted derivatives of MIX in order to determine if selectivity for inhibition of peak I activity could be achieved. The 7-substituted derivatives of MIX were prepared by treatment of 1 and the appropriate alkyl or aralkyl halide with potassium carbonate in dimethylformamide.2 The literature contains numerous reports of alkylations of theophylline to yield 7-substituted products.19•24-27 Alkylation of l-methyl-3-isobutyIxanthine (1) under these conditions afforded compounds 5-17 (Table I); the latter were assumed to be 7-substituted derivatives of 1 on the basis of the theophylline precedent and the increased steric hindrance toward alkylation at the 9xanthine nitrogen presented by the bulkier 3-isobutyl substituent.…”

Structural and Spectroscopic Characterization of Copper(II) Complexes of a New Bisamide Functionalized Imidazole Tripod and Evidence for the Formation of a Mononuclear End-On Cu−OOH Species

“…N , N -Bis((1-methyl-4-pivalamidoimidazol-2-yl)methyl)- N ‘ -((1-methylimidazol-2-yl)methyl)a mine (L2). The pale yellow oil of 1 ( 0.13 g (0.33 mmol)) in 25 mL of anhydrous methanol was reduced in the presence of 0.12 g of 5% Pd/C and 0.94 mL (1.65 mmol) of hydrazine monohydrate . After 4 h, the catalyst was carefully filtered through Celite, and the methanol filtrate was poured into 50 mL of water.…”

Hydrogen Bonding in Bis(6-amino-1,3-dimethyluracil-5-yl)-methane Derivatives: Dynamic NMR and DFT Evaluation

“…Uracil molecule is an important structural unit in wide variety of natural and synthetic compounds which have the broad spectrum of biological and medical applications. 6-Aminouracils are key intermediates in the synthesis of a number of xanthene based drug molecules and also act as starting compounds for the synthesis of new condensed heterocycles exhibiting intriguing pharmacological activities. , The most important property determining their biological and physicochemical behavior is the ability of these molecules to form hydrogen bonds.…”