43076-30-8

Usage

Uses

Used in Pharmaceutical Industry:
4'-tert-butyl-4-[4-(hydroxybenzhydryl)piperidino]butyrophenone is used as an active pharmaceutical ingredient for the treatment of allergic rhinitis. It is a derivative of Terfenadine, which is the first nonsedating antihistamine, providing effective relief from allergy symptoms without causing drowsiness.
Used in Antiviral Applications:
In the field of antiviral research, 4'-tert-butyl-4-[4-(hydroxybenzhydryl)piperidino]butyrophenone has been identified as an inhibitor of the human CD81-receptor HCV-E2 interaction. This interaction is crucial for the entry of the Hepatitis C virus (HCV) into host cells. By inhibiting this interaction, the compound can potentially prevent the viral infection and serve as a therapeutic agent against Hepatitis C.

Upstream product

• 50679-08-8 terfenadine 
• 43076-61-5 4'-tert-butyl-4-chlorobutyrophenone 
• 1057648-42-6 4-bromo-1-(4-tert-butylphenyl)butan-1-one 
• 115-46-8 C₁₈H₂₁NO 
• 253185-03-4 tert-butylbenzene 

Downstream Products

• 76811-98-8 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid 
• 50679-08-8 terfenadine 

Relevant academic research and scientific papers

Mechanism of block of a human cardiac potassium channel by terfenadine racemate and enantiomers

1. The cardiac toxicity of racemic terfenadine (marked QT prolongation and polymorphic ventricular arrhythmias) is probably due to potassium channel blockade. To test whether one of its enantiomers would be a less efficient potassium channel blocker, we compared the mechanism of action of the racemate with that of the individual enantiomers. 2. We synthesized the individual enantiomers of terfenadine and examined under whole cell voltage-clamp conditions the mechanism of action of the racemate, both enantiomers and a major metabolite on a cloned human cardiac potassium channel, hKv1.5. This delayed rectifier is sensitive to quinidine, clofilium and other 'class III' antiarrhythmic drugs at clinically relevant concentrations. 3. Upon depolarization, racemic terfenadine and its enantiomers induced a fast decline of hKv1.5 current towards a reduced steady state current level. During subsequent repolarization the tail currents deactivated more slowly than the control, resulting in a 'crossover' phenomenon. 4. The voltage-dependence of block was biphasic with a steep increase in block over the voltage range of channel opening (-30 to 0 mV), and a more shallow phase positive to 0 mV (where the channel is fully open). The latter was consistent with a binding reaction sensing 21% of the transmembrane electrical field (with reference to the cell interior). 5. The EC50 for hKv1.5 block by racemic terfenadine was 0.88 μM, while the values for R- and S-terfenadine were 1.19 μM and 1.16 μM, respectively. In contrast, the acid metabolite reduced hKv1.5 current by only 5% at a concentration of 50 μM. 6. These findings suggest that terfenadine blocks the hKv1.5 channel after it opens by entering into the internal mouth of the channel. We have previously shown that quinidine blocks hKv1.5 in a similar manner but with an apparent affinity of ~6 μM. Thus, terfenadine and its enantiomers are approximately equipotent open state blockers of this human K+ channel and about 6 times more potent than quinidine. The similar state-, time-, and voltage-dependence of hKv1.5 block by both enantiomers also indicates that the chiral centre does not significantly constrain the orientation of critical binding determinants of terfenadine with respect to the receptor site.

Chemoselective Continuous Ru-Catalyzed Hydrogen-Transfer Oppenauer-Type Oxidation of Secondary Alcohols

A continuous flow method for the selective oxidation of secondary alcohols is reported. The method is based on an Oppenauer-type ruthenium-catalyzed hydrogen-transfer process that uses acetone as both solvent and oxidant. The process utilizes a low loading (1 mol%) of the commercially available ruthenium catalyst [Ru(p-cymene)Cl2]2 and triethylamine as a base and can be successfully applied to a range of different substrates, with a good level of functional group tolerance.

METHODS AND COMPOSITIONS FOR TREATING INFECTION

Provided herein are compositions and methods for treating or preventing infection.

Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus

Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.

Biooxidation of methyl group: application to the preparation of alcohol and acid metabolites of terfenadine, ebastine and analogues

The aim of this study was to found the best conditions to prepare metabolites of terfenadine, ebastine and analogues. For that purpose we investigated the structural substrate requirements needed for the oxidative whole cell activity and selected the most efficient conditions to obtain each compound. Our results showed that either alcohol or acid derivative arising from the oxidation of a methyl group is the main product, ratio depending on the microorganism used and on the culture conditions of cells. The oxidized metabolites were synthesized at preparative scale and isolated in 35-88% yield before characterization.

Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: Synthesis and structure optimization

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert- butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27 % inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identfied as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.

Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2

The active site topology, substrate specificity, and biological roles of the human cytochrome P450 CYP2J2, which is mainly expressed in the cardiovascular system, are poorly known even though recent data suggest that it could be a novel biomarker and potential target for therapy of human cancer. This paper reports a first series of high-affinity, selective CYP2J2 inhibitors that are related to terfenadine, with Ki values as low as 160 nM, that should be useful tools to determine the biological roles of CYP2J2.

Structure-activity relationships within a series of analogues of the histamine H1-antagonist terfenadine

A number of terfenadine derivatives including terfenadine enantiomers were synthesized and tested for histamine H1-receptor affinity. No significant differences in H1 activity were found between terfenadine enantiomers. Qualitative structure-activity relationship studies identified the α,α-diphenyl-4-piperidinomethanol moiety as the pharmacophore for the H1 activity of this group of compounds. The major role of the phenylbutanol moiety in terfenadine seems to be preventing the compound from crossing the blood-brain barrier.