Modified peptides for use in treating neurodegenerative disorders
Inventors
Greenfield, Susan • GARCIA-RATES, Sara • MORAL, Jesus Seco • COSANO, Roger Prades
Assignees
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Publication Number
US-11939398-B2
Publication Date
2024-03-26
Expiration Date
Abstract
The invention relates to neurodegenerative disorders, and in particular to novel peptides, peptidomimetics, compositions, therapies and methods for treating such conditions, for example Alzheimer's disease.
Core Innovation
The invention relates to compounds of Formula (I) and related substituted variants, including Formula (Ia) and related sub-formulas, with defined substituent constraints for R1-R11 and variable index n. The compounds include pharmaceutically acceptable salts, solvates, tautomeric forms, and polymorphic forms, and preferred embodiments are further narrowed to specific formula variants and named examples.
The disclosed embodiments specify substituent relationships and embedded ring-closure structures for selected R groups, including constraints on R3, R4, R5, R6, and R7, as well as options for aryl, heteroaryl, alkyl, alkenyl, and carbonyl-containing aryl groups. Preferred embodiments include compound subformulas 101/102/103/104/105 and 101a/102a/103a/104b/105a, including named Tri02-06 examples.
The invention relates to treating or ameliorating neurodegenerative disorders, particularly Alzheimer’s disease, by administering a therapeutically effective amount of a compound of Formula (I). The therapeutic rationale is associated with interaction with the α7 nicotinic acetylcholine receptor (α7 nAChR), inhibition of toxic non-classical effects of acetylcholinesterase-derived peptides including T14/T30, reduced calcium influx and AChE activity, and lowered amyloid beta production.
Claims Coverage
The claim coverage centers on one independent method claim directed to treating or ameliorating Alzheimer’s disease by administering a therapeutically effective amount of a Formula (I) compound. The inventive features across the items total six main features, with dependent claims narrowing the compound to specific formula variants and substituent constraints.
Alzheimer’s disease treatment by administering Formula (I) compounds
Administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of Formula (I) having specified substituent relationships, where R1 is —NR9R10 or —OH, R11 is an aryl group, each n is 0, 1, 2, 3, or 4, and the remaining substituent constraints are defined as recited.
Formula (Ia) compound species
The method is carried out using a compound of Formula (Ia).
R1 fixed to —NH2
The method is further specified such that R1 is —NH2.
Substituent limitation for R2, R4, and R6
The method is further limited such that R2, R4, and R6 each have specific structures as shown by the embedded images.
Formula (101) or Formula (103) restriction
The method is wherein the compound is a compound of Formula (101) or Formula (103).
Formula (101a) or Formula (103a) restriction
The method is carried out using a compound that is either a compound of Formula (101a) or Formula (103a).
Overall, the claims are directed to administering Formula (I) compounds with defined substituent constraints to treat or ameliorate Alzheimer’s disease, with dependent claims narrowing the administered species to specific named formula variants, including Formula (Ia), Formula (101)/(103), and Formula (101a)/(103a), and further constraining substituents such as R1 = —NH2 and defined structures for R2, R4, and R6.
Stated Advantages
Inhibits toxic, non-classical effects of AChE-derived peptides T14/T30.
Reduces calcium influx and AChE activity.
Lowers amyloid beta production.
Documented Applications
Treating or ameliorating Alzheimer’s disease in a subject in need of such treatment using compounds of Formula (I) and related substituted variants.
Therapeutic use in neurodegenerative disorders including Alzheimer’s disease, with a referenced rationale connected to blood-brain barrier (BBB) crossing.
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