Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
Inventors
Wainer, Irving William • Zhu, Weizhong • Chakir, Khalid • Xiao, Rui-Ping • Abernethy, Darrell R. • Beigi Abhari, Farideh M.
Assignees
US Department of Health and Human Services
Publication Number
US-10562843-B2
Publication Date
2020-02-18
Expiration Date
2027-08-10
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Abstract
This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogues which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogues, and methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.
Core Innovation
This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogues which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided throughout the disclosure. Pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogues are also provided, along with methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.
Fenoterol is a β2-adrenergic receptor agonist traditionally used for pulmonary disorders such as asthma. It possesses two chiral carbons allowing for four stereoisomers, with commercial fenoterol formulated as a racemic mixture of (R,R)- and (S,S)-compounds. Pharmacological studies have demonstrated that the bronchodilatory activity primarily resides in the (R,R)-isomer, while the inactive (S,S)-diastereomer is associated with adverse effects and tolerance development.
The problem addressed is the need to provide fenoterol compositions effective in treating disorders such as asthma, chronic obstructive pulmonary disease, or congestive heart failure with reduced side effects such as hypersensitivity and drug resistance observed with racemic fenoterol. The disclosure provides substantially purified (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues with comparable or greater β2-adrenergic receptor activity, anticipated to reduce side effects by eliminating inactive enantiomers and allowing lower therapeutic dosages.
Claims Coverage
The claims include one independent claim focusing on a compound of a specified formula and its pharmaceutical compositions, with several dependent claims defining particular substituents and configurations. The inventive features encompass the chemical structure details and pharmaceutical compositions incorporating these compounds.
Compound defined by specific substituents
A compound characterized by a formula wherein substituents R1-R3 independently are hydrogen, acyl, alkoxy carbonyl, amino carbonyl or a combination thereof; R4 is hydrogen or lower alkyl; R5 is a lower alkyl derivative including phenyl or naphthyl substituents optionally substituted; and X, Y1, Y2, Y3 independently are hydrogen, —OR6, or —NR7R8 with further definitions for R6, R7, and R8.
Optical isomer configurations
The compound is specified as having an (R,R′)- or (R,S′)-configuration at the chiral centers.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising the defined compound and at least one pharmaceutically acceptable carrier suitable for administration.
The claims cover novel fenoterol compounds having specified substituents and chiral configurations, along with pharmaceutical compositions containing these compounds, supporting their use in therapeutics centered on β2-adrenergic receptor agonism.
Stated Advantages
Fenoterol analogues with comparable or higher efficacy than racemic fenoterol allowing potentially lower therapeutic doses.
Reduced side effects such as hypersensitivity and drug resistance due to removal of inactive enantiomers.
Higher binding affinity and selectivity for β2-adrenergic receptors compared to commercially available fenoterol.
Enhanced pharmacokinetic properties including higher systemic exposure and longer clearance time for certain analogues, potentially leading to longer-acting drugs.
Documented Applications
Use of (R,R)-fenoterol and fenoterol analogues for treating cardiac disorders, including congestive heart failure.
Use of (R,R)-fenoterol and fenoterol analogues for treating pulmonary disorders such as asthma and chronic obstructive pulmonary disease.
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