Substituted cycloalkanes for managing nephrogenic diabetes insipidus
Inventors
Sands, Jeff • Klein, Janet • Khanna, Ish • Pillarisetti, Sivaram
Assignees
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Publication Number
US-11179354-B2
Publication Date
2021-11-23
Expiration Date
Abstract
In certain embodiments, this disclosure relates to methods of treating or preventing nephrogenic diabetes insipidus comprising administering an effective amount of a compound of Formula (I) 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 document discloses methods to treat or prevent nephrogenic diabetes insipidus (NDI) in a subject in need thereof. The methods comprise administering a therapeutically effective amount of a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, derivative, or salt of the compound.
The compounds are substituted cycloalkane compounds of Formula I, with stereoisomers, derivatives, and salts, and are illustrated by compounds referred to as NDI-5001, NDI-5033, and NDI-5037. The document links activity to AMPK-activator activity supporting UT-A1 and AQP2 phosphorylation, targeting NDI symptoms including dilute urine, excessive urination, and excessive thirst.
The document includes diagnostic and response metrics associated with improvement, including urine osmolality and reductions in urine volume and urination frequency. It also describes combination therapy options with other named active agents, and reports in vivo performance in a tolvaptan-induced NDI model and V2R knockout mice, including sustained anti-diuretic response and improved urine concentrating ability.
Claims Coverage
The document provides one independent claim describing a method for treating nephrogenic diabetes insipidus by administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula I (or a pharmaceutically acceptable salt). The inventive features are further refined by dependent claims that specify NDI subtypes, effectiveness thresholds, urine osmolality targets, safety-related outcomes, and optional combination therapy with selected second active agents.
Treating nephrogenic diabetes insipidus with a Formula I compound pharmaceutical composition
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 a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Formula I substituted cycloalkane compound structure
The administered compound is a compound of Formula I having the structural definitions in the claim, including L being -(CH2)10-14; R1 and R2 being NHR′ or OH; R3 and R4 forming a C3-5 carbocyclyl together with the attached carbon; R5 and R6 forming a C3-5 carbocyclyl together with the attached carbon; each R′ being independently H or cycloalkyl; and n independently being 0.
Urine concentrating effectiveness thresholds
In the dependent claim set, effectiveness is defined using quantitative outcomes including reduction of daily urine volume (e.g., about 50%) and urine osmolality greater than 125 mOsm/kg.
NDI subtype and specific etiology refinement
The treated condition is refined in dependent claims to acquired nephrogenic diabetes insipidus and further refined to nephrogenic diabetes insipidus induced by lithium therapy.
Combination therapy with selected second active agents
The method may include a combination therapy option where a second active agent is selected from an AMP-activated protein kinase activator, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, a diuretic, or a P2Y purinergic receptor antagonist.
Overall, the claim coverage centers on treating NDI by administering a pharmaceutical composition containing a pharmaceutically acceptable excipient and a Formula I substituted cycloalkane compound (or pharmaceutically acceptable salt). Dependent claim refinements specify structural context, NDI subtypes and etiology, quantitative urine osmolality and urine volume/frequency outcomes, and optional combination therapy with selected classes of second active agents.
Stated Advantages
Improved urine concentrating ability as reflected by urine osmolality and reductions in urine volume/frequency, including sustained anti-diuretic response.
Treatment targets NDI symptoms including dilute urine, excessive urination, and excessive thirst.
Claims include safety-related refinements describing no hypoglycemia and no gastrointestinal distress in the referenced embodiments.
Documented Applications
Use of the claimed method(s) to treat or prevent nephrogenic diabetes insipidus in a subject in need thereof, including acquired NDI and lithium-induced NDI.
Use of combination therapy as described with a second active agent selected from an AMP-activated protein kinase activator, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, a diuretic, or a P2Y purinergic receptor antagonist.
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