Quinoline amides and methods of using same
Inventors
MIRANKER, Andrew • Kumar, Sunil
Assignees
Publication Number
US-12336987-B2
Publication Date
2025-06-24
Expiration Date
2036-10-27
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Abstract
The present invention provides novel compounds that are quinoline foldamers. Such foldamers stabilize and bind to islet amyloid polypeptide (IAPP). In certain embodiments, the quinoline foldamers of the invention are soluble and cross biological membranes without cellular assistance. The present invention further provides novel methods of preventing or treating diabetes in a subject in need thereof by administering to the subject an effective amount of at least one quinoline foldamer of the invention. The present invention further provides novel methods of preventing or treating a neurodegenerative disease caused by a misfolded and/or unstructured protein in a subject in need thereof by administering to the subject an effective amount of at least one quinoline foldamer of the invention.
Core Innovation
The invention provides novel quinoline foldamers that are capable of stabilizing and binding to islet amyloid polypeptide (IAPP). These foldamers are designed to prevent the formation of toxic amyloid states of IAPP in mammals. In certain cases, the quinoline foldamers are water soluble and can cross biological membranes without cellular assistance, which may contribute to their biological utility.
The present invention addresses a need in the art for new foldamers that can be used to treat diseases in mammals, such as diabetes and neurodegenerative diseases caused by misfolded and/or unstructured proteins. Previous challenges in targeting disordered proteins relevant to diseases like Alzheimer's and Parkinson's have limited structure-targeted therapeutics. The quinoline foldamers of this invention overcome these challenges by capturing structure in disease-associated peptides and stabilizing non-toxic conformers.
These compounds include tetraquinolines that stabilize a pre-amyloid, α-helical conformation of IAPP, and are designed to dock specifically with intracellular IAPP to rescue cells from apoptosis. The compounds are also capable of being conjugated to various biologically active molecules, resulting in improved membrane permeability of these conjugates. The invention further includes pharmaceutical compositions, methods for preventing or treating diabetes or neurodegenerative diseases, and methods for increasing the membrane permeability of molecules.
Claims Coverage
There is one independent claim in the patent, with dependent claims that specify further embodiments. The main inventive features focus on the use of quinoline foldamers to treat diabetes.
Method of ameliorating or treating diabetes with quinoline foldamers
A method comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I), or a salt, solvate, or N-oxide thereof, which is a quinoline foldamer characterized by: - Each occurrence of R1 independently selected from —OH, —O(C1-C6)alkyl, —O(C1-C6)haloalkyl, —O(C1-C6)heteroalkyl, —O(CH2)mC(═O)OR5, —OC(═O)R5, —NH2, —SH, —SO3H and —PO(OH)2. - R2 selected from —(C1-C6)alkyl, —(C1-C6)heteroalkyl, —OR5, —(C3-C10)heterocyclyl, aryl and heteroaryl, with optional substitution as described. - R3 and R4 independently selected from H, —(C═O)0-1(C1-C6)alkyl, —(C═O)0-1(C3-C5)cycloalkyl, —(C═O)0-1(C1-C6)heteroalkyl, —(C═O)0-1aryl, and —(C═O)0-1heteroaryl, with optional substitution; or together form —(C3-C10)heterocyclyl or —NO2. - Each occurrence of R5 independently selected from H, —(C1-C6)alkyl, —(C1-C6)heteroalkyl, —(C3-C5)cycloalkyl, —(C4-C10)heterocyclyl, aryl, and —(C5-C10)heteroaryl, with optional substitution. - Each occurrence of m is an integer from 1 to 5; k is an integer from 1 to 5. - The compound has a net negative charge at physiological pH. The invention is directed to administration for the purpose of ameliorating or treating diabetes.
The claims cover a method of treating or ameliorating diabetes by administering specific quinoline foldamers with defined chemical features, providing broad protection for compositions and methods involving these compounds.
Stated Advantages
The compounds are highly soluble and capable of passively penetrating cell membranes without cellular assistance.
Quinoline foldamers specifically bind to IAPP and prevent the formation of toxic amyloid states.
The compounds can rescue cells from apoptosis induced by toxic forms of IAPP.
Foldamers can be conjugated to biologically active molecules to improve cell membrane permeability of those molecules.
The compounds stabilize non-toxic conformers of disease relevant peptides to offer a strategy for cytotoxic rescue.
Documented Applications
Preventing or treating diabetes in a subject by administering quinoline foldamers.
Preventing or treating neurodegenerative diseases caused by misfolded or unstructured proteins, including diseases involving α-synuclein (Parkinson's), tau or Aβ (Alzheimer's).
Increasing the cell membrane permeability of molecules such as oligonucleotides, oligodeoxynucleotides, small molecules, or polypeptides by derivatization with a quinoline foldamer.
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