Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 microM) and 5'-amino-5'-deoxyadenosine (IC50 = 0.17 microM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5'-Amino-5'-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50S < 0.001 microM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay.
In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 microM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected alpha-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED50s < or = 2.0 mg/kg, ip, and showed relatively mild side effects.
Product yields were determined for the reactions of cis-stilbene with C6F510 in CH2CI2 with (meso-tetrakis(pentafluorophenyl)porphinato)iron(III) chloride [( FmTPP)Fel*'(Cl)], (meso-tetrakis(2,6-dichlorophenyl)po~hinato)iron(IIl) chloride [ (ClsTPP)Fe"'(CI) J , and (meso-tetrakis(2,6-dichlorophenyl)porphinato)mangan~e(Ill) chloride [ (CI,TPP)Mn"'(CI)] as catalysts.Because they provided less cis-stilbene destruction and best yields of cis-stilbene oxide, the above catalysts and solvent were chosen from a number of systems investigated. cis-Stilbene destruction was found to exceed the C6F510 oxidant employed. Aside from cis-stilbene, the products cis-stilbene oxide, trans-stilbene, trans-stilbene oxide, diphenylacetaldehyde (DPhA), deoxybenzoin (DEB), and PhCHO were quantified. These products do not arise from cis-stilbene oxide. In the absence of 02, yields of PhCHO decreased, yields of trans-stilbene and cis-stilbene oxide increased, and destruction of cis-stilbene (to unaccountable products) decreased. Formation of PhCHO and destruction of cis-stilbene are explained by 1 e-oxidation of cis-stilbene to a carbocation radical (1). Reaction of 1 with 0, results in the formation of PhCHO and radical polymerization
A novel shape-feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries. The method is applied to two thrombin data sets and is shown to be efficient in identifying novel scaffolds with enhanced hit rates.
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