Sulfopropanoic acid derivatives for treating neurodegenerative disorders
Inventors
Kocis, Petr • Hey, John • TOLAR, Martin
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12285400-B2
Publication Date
2025-04-29
Expiration Date
Abstract
Provided herein is the use of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, for treating a disease characterized by amyloid and amyloid-like aggregates, e.g., Alzheimer's disease.
Core Innovation
The invention relates to a method of treating a subject suffering from Alzheimer’s disease by administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The compounds are defined by specific structural relationships in which R1, R2, R3, R4, R5, R6, R7, and R8 are selected according to defined options and substitution rules.
The defined Formula I structural framework includes selection rules for R1 and R2, with R1 selected from O-R3, O-R4-CH(NHR6)-C(O)-R5, and [N(R6)-CH(R7)-C(O)]1-2-R5, and R2 selected from hydrogen, R3, or R4-CH(NHR6)-C(O)-O-R5. R3 is selected from multiple alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and alkylene-linked options, each optionally substituted within defined limits, and R1 and R2 each comprise no more than 2 cyclic moieties.
The method also relies on a defined side-chain composition, where R6 is hydrogen or C(O)R8, R7 is a side chain of an α-amino acid, and R8 is hydrogen, C1-C4 alkyl, O-C1-C4 alkyl, (C1-C4 alkylene)-aryl, or (C1-C4 alkoxy)-aryl. The disclosure also frames the treatment around 3-sulfopropanoic acid (3-SPA), CSF biomarker measurements, baseline-threshold concepts for subject selection and treatment, and multiple specific Formula I compounds and related variants in the context of Alzheimer's disease treatment.
Claims Coverage
The consolidated content includes one independent claim directed to a treatment method for Alzheimer's disease. The inventive features are the administration of an effective amount of a Formula I compound or pharmaceutically acceptable salt, together with the defined Formula I substituent selection rules and the limits on cyclic moieties, with dependent criteria including baseline-threshold, ApoE4 status, and MMSE-based eligibility refinements.
Alzheimer’s disease treatment by administering a Formula I compound
A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Formula I scaffold with constrained substituent selection rules
A compound of Formula I wherein R1 is selected from O-R3, O-R4-CH(NHR6)-C(O)-R5, and [N(R6)-CH(R7)-C(O)]1-2-R5; R2 is selected from hydrogen, R3, and R4-CH(NHR6)-C(O)-O-R5; R3 is independently selected from the specified alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and alkylene-linked options; R4 is independently selected from -CH(CH3)- and -CH2-; R5 is independently selected from -OH, -O-C1-C4 alkyl, and -NH2; R6 is independently selected from hydrogen and -C(O)R8; R7 is a side chain of an α-amino acid; and R8 is independently selected from hydrogen, C1-C4 alkyl, -O-C1-C4 alkyl, (C1-C4 alkylene)-aryl, and (C1-C4 alkoxy)-aryl.
Optional substitution limits for R3 and ring portions
Each alkyl, alkenyl, or alkynyl portion of R3 is optionally substituted with up to 6 substituents independently selected from halo, -OH, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), carbocyclyl, aryl, heterocyclyl, and heteroaryl; each carbocyclyl, aryl, heterocyclyl, or heteroaryl portion of R3 is optionally substituted with up to four substituents selected from halo, -OH, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), C1-C18 alkyl, C2-C18 alkenyl, and C2-C18 alkynyl.
Limits on cyclic moieties for R1 and R2
R1 comprises no more than 2 cyclic moieties and R2 comprises no more than 2 cyclic moieties.
Baseline-threshold determination prior to treatment
The method treats a subject only after determining that the subject’s endogenous level of a compound having the specified chemical formula is below a predetermined baseline threshold prior to treatment.
ApoE4 genotype eligibility for treatment
Administering the Formula I compound to a subject whose ApoE4/4 status is specified as ApoE4/4 homozygous.
MMSE score eligibility for treatment
Administering the Formula I compound to subjects whose pre-treatment MMSE score is specified within a range of 22 to 28.
Overall claim coverage centers on an Alzheimer's disease treatment method that administers an effective amount of a Formula I compound with extensive, explicitly defined substituent selection rules and substitution caps, together with explicit limits on the number of cyclic moieties in R1 and R2.
Stated Advantages
Inhibits Aβ42 aggregation into small oligomers.
3-SPA inversely correlates with cognitive impairment severity as assessed by MMSE.
Baseline threshold selection and administration of Formula I prodrugs or salts are used to raise and maintain CSF 3-SPA above a threshold for treatment, prevention, and decelt of cognitive decline.
Documented Applications
A method of treating a subject suffering from Alzheimer's disease by administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Treatment guidance framed as prevention and decelt of cognitive decline using baseline-threshold selection and maintaining CSF 3-SPA above a threshold.
Alzheimer’s disease diagnosis/monitoring embodiments using biomarker-informed criteria including CSF biomarkers (Abeta peptides, tau, Abeta oligomers), brain amyloid PET imaging, CDR, and FCSR memory test.
Interested in licensing this patent?