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Abstract

Enhanced brain delivery of zidovudine (AZT) has been demonstrated using a redox-based chemical delivery system (CDS). Optimization of the prototype AZT-CDS (5'-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]-3'-azido-3'-deoxy thymidine ) was investigated by manipulation of the N-methyl group present on the dihydronicotinate portion of the molecule and examining the release of AZT in vivo in a rat model. Of the five compounds examined, all produced higher brain levels and lower blood levels of AZT than did AZT itself. In comparing the novel AZT-CDS analogues to the N-methyl benchmark, the N-propyl system proved to be the most efficient of the compounds tested.

Targeting drugs to the brain by redox chemical delivery systems

“…10). 145 While systemic administration of 27 (17-CDS) produced high levels of the corresponding quaternary pyridinium compound (28) in the brain of rats that could be followed analytically over the 14-day time course of the experiment, 29 resulted in no signi®cant amount of quaternary ion (30) trapping, as shown in Table I. The peripheral burden of estradiol was similar for the two forms of CDS with total estradiol (26) area under the curve (AUC) of 168.8 and 160 ng Á day/ml serum after administration (5 mg/kg) of 27 and 29, respectively.…”

“…The effect of the N-alkyl substitution (Et, Pro, iPr, Bz) on the ef®cacy of the CDS was also investigated. 174 Subsequent to the studies on rats, 34a was also evaluated in dog model. Mongrel dogs (20 kg body weight) were given 110 mmol/kg AZT in a vehicle containing 2.5% dimethyl sulfoxide in polyethylene glycol (PEG 400) followed by a dose of 11 mmol/kg of CDS one week later.…”

Ester Derivatives of Nucleoside Inhibitors of Reverse Transcriptase: 1. Molecular Transport Systems for 3′-Azido-3′-Deoxythymidine and 2′,3′-Didehydro-3′-Deoxythymidine

“…A consideration of all the results led to the synthesis of the 1,4-dihydropyrinine derivatives (LVIb)-(LVIf) with various substituents at the nitrogen of pyridine cycle [65] (Scheme 10). An elongation of N-alkyl chain was supposed to increase lipophylicity and remain almost unchanged the stability of derivatives, whereas the introduction of benzyl group was presumed to increase the stability of the delivery system to oxidation.…”

Identification of a More Potent Analogue of the Naturally Occurring Alkaloid Huperzine A. Predictive Molecular Modeling of Its Interaction with AChE

“…The work reveals the type of modification that confers increased AChE inhibitory potency to the product; specifically, a lipophilic substituent capable of providing additional hydrophobic contacts with the enzyme. Additionally, in view of the fact that the calculated log P of the methyl analogue is 0.82 versus 0.44 for huperzine, the new analogue may exhibit an improved therapeutic profile through its increased ability to penetrate the blood brain barrier …”