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-10308591-B2
Publication Date
2019-06-04
Expiration Date
2027-08-10
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Abstract
This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogs which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogs are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogs, 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 concerns 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 analogues are provided, along with pharmaceutical compositions containing these compounds and methods for their use in treating cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.
Fenoterol, a β2-adrenergic receptor agonist, has traditionally been used in treating pulmonary disorders like asthma. It exists in four stereoisomeric forms due to having two chiral carbons, and is commercially available as a racemic mixture of the (R,R) and (S,S) forms. It has been demonstrated that the primary bronchodilatory activity in racemic fenoterol resides in the (R,R) isomer, whereas the (S,S)-diastereomer can cause adverse side effects or development of tolerance.
The problem addressed is the unwanted side effects, such as hypersensitivity and drug resistance, arising from the inactive or less active enantiomer in racemic fenoterol formulations. Therefore, it is advantageous to provide fenoterol compositions that effectively treat respiratory and cardiac disorders with reduced side effects. This disclosure solves this problem by preparing substantially purified (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues, demonstrating their efficacy in treating congestive heart failure and pulmonary disorders, with lower incidence of side effects due to removal of the inactive enantiomers.
Claims Coverage
The patent includes four inventive features derived from an independent method claim relating to treating congestive heart failure by administering specific fenoterol compounds or compositions.
Use of specific fenoterol compound for treatment of congestive heart failure
Administering to a subject with congestive heart failure a therapeutically effective amount of a compound defined by a specific chemical formula representing (R,R)-fenoterol or analogous structures.
Utilization of pharmaceutical composition comprising the fenoterol compound
Administering the therapeutically effective amount of the specified fenoterol compound as part of a pharmaceutical composition which includes at least one pharmaceutically acceptable carrier.
Increase of cardiomyocyte contractility by fenoterol compound administration
Administering the therapeutically effective amount of the specified fenoterol compound to increase cardiomyocyte contractility thereby treating congestive heart failure.
The claims principally cover methods of treating congestive heart failure using (R,R)-fenoterol or its analogues administered in therapeutically effective amounts, including formulations with pharmaceutically acceptable carriers, and specifically highlight the effect of increasing cardiomyocyte contractility.
Stated Advantages
Use of (R,R)-fenoterol or fenoterol analogues can reduce side effects such as hypersensitivity and drug resistance compared to racemic fenoterol.
The disclosed compounds have equal to or greater β2-adrenergic receptor binding affinity and efficacy compared to commercially available fenoterol.
Certain fenoterol analogues exhibit longer systemic exposure and slower clearance, potentially providing longer acting treatments.
Pharmaceutical compositions including substantially pure enantiomers reduce adverse effects caused by inactive stereoisomers.
Documented Applications
Treatment of cardiac disorders such as congestive heart failure using (R,R)-fenoterol and fenoterol analogues.
Treatment of pulmonary disorders such as asthma and chronic obstructive pulmonary disease using fenoterol analogues.
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