Compounds for increasing the nicotinamide adenine dinucleotide in a subject and methods of use thereof
Inventors
GORDON-BLAKE, Jesse • DRIVER, Tom G. • RATIA, Kiira • Thatcher, Gregory R. • WEIDIG, Victoria • Tai, Leon
Assignees
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Publication Number
US-12552760-B2
Publication Date
2026-02-17
Expiration Date
Abstract
In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds that increase the amount of nicotinamide adenine dinucleotide (NAD+) in a subject. By raising the amount of nicotinamide adenine dinucleotide in a subject, diseases associated with reduced levels of nicotinamide adenine dinucleotide can be treated or prevented. In one aspect, raising the amount of NAD+ in a subject can reduce or ameliorate one or more symptoms of Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple sclerosis, amylotrophic lateral sclerosis, AIDS-induced dementia, or epilepsy.
Core Innovation
The disclosure relates to compounds and pharmaceutically acceptable salts thereof that increase cellular NAD+ for treating or preventing neurological diseases. The patent describes the discovery and characterization of NAMPT positive allosteric modulators (N-PAMs) identified via HTS, including a representative compound NP-A3-B2, and a high-resolution NP-A3-B2:NAMPT co-crystal structure showing binding in a NAMPT rear allosteric channel.
The disclosure frames the compound structures around structure I and describes variable substituents on the structure using R1, R2, and R3, with indices r, s, and t. Additional labeled structural forms, including structure II, structure III, and structure IV, are described using constrained substituent classes and variable settings, while structure-activity relationships are organized using three SAR regions, R1, R2, and R3.
The disclosure addresses NAD+ biosynthesis and emphasizes NAD+ enhancement through pathways including Preiss-Handler, de novo, and salvage via NAMPT. It reports that synthesized NAMPT activator analogs increase cellular NAD+ and mitigate oxidative stress in cellular models, and it includes pharmaceutical composition and administration context described as non-limiting with pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.
Claims Coverage
The provided claim coverage centers on one independent claim directed to a chemical compound defined by structure I or a pharmaceutically acceptable salt thereof. The inventive features are the structure I scaffold with defined R1, R2, and R3 substituent classes and the index ranges r, s, and t, with dependent coverage refining sub-forms and therapeutic use.
Structure I compound with defined R1, R2, and R3 substituent classes
A compound having a structure I or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl group substituted with at least one alkoxy group, haloalkoxy group, hydroxyl group, alkyl group, haloalkyl group, or an amino group; R2 is a substituted or unsubstituted heteroaryl group selected from specified heteroaryl groups including substituted monocyclic heteroaryl substituted with alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, and thiol; and R3 is a substituted or unsubstituted tetrahydropyranyl group substituted with groups selected from alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, and thiol, with r being 1, 2, or 3; s being 1, 2, or 3; and t being 0, 1, or 2.
The core inventive coverage is a structure-based chemical definition combining a substituted phenyl R1, a selected substituted or unsubstituted heteroaryl R2, and a substituted tetrahydropyranyl R3 with constrained index variables r, s, and t. The claim-related content also includes pharmaceutical composition and treating or preventing neurological diseases by administering the claimed compound to a subject.
Stated Advantages
Increases cellular NAD+.
Mitigates oxidative stress, including ROS attenuation.
Increases NAMPT activity, as indicated by EC50/Amax comparisons.
Documented Applications
Treating or preventing neurological diseases in a subject by administering the compound, including Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, ALS-induced dementia, AIDS-induced dementia, and epilepsy.
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