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-9522871-B2
Publication Date
2016-12-20
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 invention discloses the discovery and preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues that are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures of these fenoterol analogues are provided, and pharmaceutical compositions containing them are described. Methods of using such compounds and compositions to treat cardiac disorders such as congestive heart failure and pulmonary disorders including asthma or chronic obstructive pulmonary disease are also provided.
The problem addressed is that fenoterol, a β2-adrenergic receptor agonist traditionally used to treat pulmonary disorders such as asthma, exists as a racemic mixture containing (R,R) and (S,S) stereoisomers, with only the (R,R) isomer producing bronchodilation. The inactive (S,S) enantiomer may cause adverse effects like hypersensitivity, tolerance, or drug resistance. Therefore, there is a need for fenoterol compositions that retain therapeutic efficacy while reducing side effects associated with the inactive enantiomer.
The invention purifies (R,R)-fenoterol and fenoterol analogues to more than 90% purity from racemic mixtures, removing inactive enantiomer contaminants that contribute to adverse effects. These analogues exhibit comparable or greater efficacy than racemic fenoterol and can be used to treat cardiac disorders such as congestive heart failure, offering an advantage of reduced side effects due to the absence of physiologically less active forms.
Claims Coverage
The claims include one independent claim covering a specific compound of the invention, and thus involve one main inventive feature.
Compound having the name (R,R′)-4-methoxy-ethylfenoterol
The invention includes the compound named (R,R′)-4-methoxy-ethylfenoterol as a distinct chemical entity.
The claims focus on the specific compound (R,R′)-4-methoxy-ethylfenoterol, covering its composition and stereochemistry as the main inventive feature.
Stated Advantages
Fenoterol analogues have equal or greater efficacy at β2-adrenergic receptors compared to racemic fenoterol.
Higher enantiomeric purity reduces adverse side effects such as hypersensitivity and drug resistance observed with racemic fenoterol.
Fenoterol analogues exhibit improved β2-adrenergic receptor subtype selectivity relative to β1-adrenergic receptors.
Certain fenoterol analogues show higher systemic exposure and longer clearance time, suggesting longer duration of action compared to (R,R)-fenoterol.
Documented Applications
Treatment of congestive heart failure and other cardiac disorders by administering therapeutically effective doses of (R,R)-fenoterol or (R,R)- or (R,S)-fenoterol analogues.
Treatment of pulmonary disorders such as asthma and chronic obstructive pulmonary disease with therapeutically effective doses of (R,R)-fenoterol or (R,R)- or (R,S)-fenoterol analogues.
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