Journal of medicinal chemistry
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Physicochemical analysis and Monte Carlo simulations were used to identify structural features which prevent oral absorption of HBED, a potent iron chelator. In water the dominant conformations of HBED involve the hydrophobic collapse of the two aromatic rings. These conformations are favored in polar media because they expose the polar phenolic hydroxy groups to the solvent and partially shield the nonpolar aromatic rings. ⋯ Conformational analysis in chloroform confirmed that, in contrast to HBED, no symmetric interaction between the carboxylate and the nitrogen amines is possible in the half-ester and a variety of conformations which allow partial shielding of the polar phenolic OH groups are energetically possible. This theoretical model predicting a better solubility of the half-esters in nonpolar solvents was supported by the large increase in the partition coefficients in octanol, chloroform, and cyclohexane measured experimentally. The high absorbability predicted by physicochemical and computer simulation methods was corroborated by in vivo experiments in marmoset monkeys where the monoethyl ester derivative of HBED was well-absorbed orally while the parent compound was nearly ineffective in the same model.
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N,N'-Bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N'-diacetic acid (1) was recently described as a new type of iron chelator for protection against oxidative damage. It has a low affinity for iron, but the corresponding iron complex undergoes a site-specific oxidation by hydrogen peroxide through intramolecular aromatic hydroxylation into a highly stable iron phenolato complex, which does not catalyze hydroxyl radical formation. ⋯ These results thus demonstrate that, providing sufficient intracellular chelator concentration is reached, 1 efficiently protects cells against the deleterious effects of hydrogen peroxide. This strategy of oxidative activation should help the design of new chelators with better safety margins, which may be useful against oxidative damage under conditions where a prolonged administration is needed.
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The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure-activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.