Chromatographic Behaviour Predicts the Ability of Potential Nootropics to Permeate the Blood-Brain Barrier

The log BB parameter is the logarithm of the ratio of a compound’s equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k\u27. The second aim was to estimate the brain’s absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k\u27 were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism

Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers

Series of alkyl esters of 6-(diethylamino)-, 6-(pyrrolidin-1-yl)-, 6-(pi¬peridin-1-yl) and 6-(morpholin-4-yl)hexanoic acids and alkylamides of 6-(dimethylamino)-, 6-(piperidin-1-yl) and 6-(morpholin-4-yl)hexanoic acids, containing 8–12 carbon atoms in the alkyl chain, were prepared by methods of classical organic synthesis. The appropriate secondary amine was alkylated with ethyl 6-bromohexanoate to give ester of ω-substituted hexanoic acid, except of ethyl 6-(dimethylamino)hexanoate (1), which was prepared by Eschweiler–Clarke methylation of 6-aminohexanoic acid followed by direct esterification with ethanol. The resulted esters of ω-substituted hexanoic acids underwent direct transesterification with long chain alkanols to yield the desired amino esters, or they were treated with long-chain alkylamines to prepare secondary amides of the appropriate heterocyclic hexanoic acids. These products were in vitro tested on their activity as transdermal permeation enhancers on the strips of the excised human skin with theophylline as the model permeant. The activity was evaluated using parameter enhancement ratio (ER), defined as the ratio between the overall amount of the permeant passing through the skin with the tested enhancer and that without tested substance. Decyl 6-(pyrrolidin-1-yl)hexanoate (9) with ER = 30 showed the highest activity. The enhancing effects of the esters were generally better than those of the amides

Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers - Supplementary material

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Synthesis of 2-{[2-(2-oxo-1-azacycloalkyl)acetamido]phenoxy}acetic acids and their activity as aminopeptidase M inhibitors

Abstract: A series of 9 phenoxyacetic acids substituted in the o-, m-, and p-position of benzene ring with 2-(2-oxo-1-azacycloalkyl)acetamidic moiety containing 5–7-membered �-lactam ring was prepared by a 4-step synthetic procedure. Five selected substances of this series were tested in vitro for inhibition of porcine kidney aminopeptidase M. 2-{4-[2-(2-Oxoperhydroazepin-1-yl)acetamido]phenoxy}acetic acid exhibited the highest activity with Ki = 243.6 �M

Synthesis of 2-{[2-(2-oxo-1-azacycloalkyl)acetamido]phenoxy}acetic acids and their activity as aminopeptidase M inhibitors

A series of 9 phenoxyacetic acids substituted in the o-, m-, and p-position of benzene ring with 2-(2-oxo-1-azacycloalkyl)acetamidic moiety containing 5–7-membered w-lactam ring was prepared by a 4-step synthetic pro¬cedure. Five selected substances of this series were tested in vitro for inhibition of porcine kidney aminopeptidase M. 2-{4-[2-(2-Oxoperhydroazepin-1-yl)acetamido]phenoxy}acetic acid exhibited the highest activity with Ki = 243.6 mM

Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance

Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme