Substituted cycloalkanes for managing nephrogenic diabetes insipidus
Inventors
Sands, Jeff • Klein, Janet • Khanna, Ish • Pillarisetti, Sivaram
Assignees
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Publication Number
US-11844770-B2
Publication Date
2023-12-19
Expiration Date
Abstract
In certain embodiments, this disclosure relates to methods of treating or preventing nephrogenic diabetes insipidus comprising administering an effective amount of 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide), pharmaceutical salts or derivatives thereof, as described herein, to a subject in need thereof. in certain embodiments, the subject has been diagnosed with nephrogenic diabetes insipidus.
Core Innovation
The invention relates to treating nephrogenic diabetes insipidus (NDI) in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a Formula I substituted cycloalkane. The described compounds include 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide) and 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxylic acid), including pharmaceutically acceptable salts and stereoisomers.
The method is directed to improving urine concentrating ability and addressing NDI symptoms associated with large volumes of dilute urine, excessive urination, and thirst. The treatment is described in terms of quantitative endpoints such as increased urine osmolality and reduced urine volume.
The compositions are described as including a pharmaceutically acceptable excipient and, optionally, enabling AMPK-mediated phosphorylation of UT-A1 and AQP2 to improve urine concentrating ability. The disclosure also addresses therapeutic targets and safety/tolerability aims, including avoiding elevated urine glucose and hypoglycemia, and includes oral administration.
Claims Coverage
The claim content provides two independent claims covering treatment of nephrogenic diabetes insipidus by administering therapeutically effective amounts of specified Formula I substituted cycloalkanes with pharmaceutically acceptable excipients or salts. The claims include multiple inventive features, including the specific active compounds, quantitative treatment endpoints related to urine concentration and urination volume, lithium-induced NDI, metabolic-safety constraints, optional oral administration, and optional co-administration of a second active agent from defined classes.
Therapeutically effective composition for NDI treatment
A method for treating nephrogenic diabetes insipidus in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide) or a pharmaceutically acceptable salt thereof.
Therapeutically effective composition for NDI treatment with cyclopropane carboxylic acid
A method for treating nephrogenic diabetes insipidus in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxylic acid) or a pharmaceutically acceptable salt thereof.
Lithium-induced nephrogenic diabetes insipidus indication refinement
The method further specifies that nephrogenic diabetes insipidus is induced by lithium therapy.
Urination-volume reduction endpoint
The method includes administering to the subject such that the subject’s urination volume is reduced to less than 20 L/day.
Urine osmolality increase endpoint
The method includes administering to the subject such that the subject’s urine osmolality is greater than 125 mOsm/kg.
Metabolic-safety constraints regarding blood sugar
The method further includes administering a treatment to a subject that does not alter blood sugar levels in the subject or does not induce hypoglycemia in a fasting condition in the subject.
Optional oral administration
The method further specifies that the pharmaceutical composition is administered orally to a subject.
Selectable second active agent from defined therapeutic classes
The method includes co-administering a second active agent selected from adenosine monophosphate-activated protein kinase activators, cyclic guanosine monophosphate-specific phosphodiesterase inhibitors, diuretics, or P2Y purinergic receptor antagonists.
The core coverage is treatment of nephrogenic diabetes insipidus by administering therapeutically effective pharmaceutical compositions containing specified Formula I substituted cycloalkanes with pharmaceutically acceptable excipients or salts. The claims further narrow to lithium-induced NDI, add quantitative endpoints for reduced urination volume and increased urine osmolality, include metabolic-safety constraints regarding blood sugar and hypoglycemia, may specify oral administration, and may optionally include a second active agent selected from defined therapeutic classes.
Stated Advantages
Improves urine concentrating ability, as reflected by increased urine osmolality.
Reduces urination volume and addresses excessive urination associated with NDI.
Avoids elevated urine glucose and avoids hypoglycemia.
Documented Applications
Treatment of nephrogenic diabetes insipidus.
Treatment of lithium-induced nephrogenic diabetes insipidus.
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