Soft Drugs. 12. Design, Synthesis, and Evaluation of Soft Bufuralol Analogues

Abstract

In the search for more potent but still short-acting beta-blockers (BB), the methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 2-(1-adamantyl)ethyl, and methylthiomethyl esters of the acidic inactive metabolite of bufuralol were synthesized based on the "inactive metabolite" approach. The cleavage of the ester bond by blood and tissue esterases rapidly deactivates these compounds, resulting in an ultrashort duration of action. The beta-antagonist potencies and time courses of actions of the new "soft" BBs were characterized by recording ECG and intra-arterial blood pressure (BP) in rats. In the isoproterenol-induced tachycardia model, while bufuralol at an iv dose of 1 mg/kg (3.8 micromol/kg) diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted for only 10-30 min at equimolar dose. The inactive metabolite did not decrease HR significantly. The first four members of this series of compounds showed the highest beta-blocking potencies, ranging between 25% and 50% of that of bufuralol. Next, the effects of these most active compounds on resting HR and BP were evaluated in comparison to esmolol. Infused for 10 min at a rate of 20 micromol/kg/min, esmolol decreased HR and mean arterial pressure (MAP) by 40% and 60%, respectively. The soft drugs at doses ranging only between 2 and 4 micromol/kg/min resulted in a 20-40% decrease in HR and a 30-50% reduction in MAP. However, the time courses of both the bradycardic and hypotensive effects of the soft drugs were superimposable to that of esmolol, diminishing within 60 min after the discontinuation of the infusions.

Asymmetric Reduction of Ketones by Biocatalysis Using Clementine Mandarin (Citrus reticulata) Fruit Grown in Annaba or by Ruthenium Catalysis for Access to Both Enantiomers

“…The asymmetric reduction of heteroaryl ketones containing furan, thiophene, chroman, and thiochroman moieties is one of the most important reactions for producing chiral alcohols. The potential use of such optically enriched alcohols building blocks is vast, and includes, among others, pharmaceuticals and synthetic intermediates in organic synthesis . The catalysts for the asymmetric reduction of ketones can be classified into two categories: chemical and biological methodologies.…”

Retrometabolism‐Based Drug Design and Targeting

“…Not only does a differential metabolism of the two enantiomers occur but also differences due to genetic polymorphism are encountered [139]. A soft drug approach may help avoid these problems, and a number of ester-containing SD candidates (25) were synthesized and then tested for b-antagonist activity by recording ECG and intra-arterial blood pressure in rats [140]. This is an example of a hypothetical inactive metabolite-based approach, as the retrometabolic design starts not from an actual, major metabolite, but from a hypothetical one (26).…”

Strategies for Drug Design

“…At the same time, it undergoes rapid hydrolysis in human blood, a most important advantage, since this eliminates undesired systemic activity. Essentially the same approach was adopted more recently to design ultra-short acting, soft bufuralol analogues, which are also β-blockers [52]. In this case the aromatic moiety of the lead compound, bufuralol, contains an ethyl substituent, which is metabolised to an acetic acid group in the inactive metabolite.…”