Methods for ameliorating cognitive impairment using bile acid derivatives

A method of reversing cellular senescence associated with Parkinson's Disease in the neurons of a subject, comprising administering to the subject at least one therapeutically effective amount of a compound of formula (I)

• or a pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof, wherein:
• R1 is H, OH, alkoxy, or oxo;
• R2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R3 is H, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
• R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, or halogen, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl;
• R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl;
• R8, R9, and R10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
• m is 0, 1, or 2;
• n is 0 or 1;
• and
• p is 0 or 1.

A method of ameliorating, mitigating, treating, or preventing telomere dysfunction associated with Parkinson's Disease in the neurons of a subject, comprising administering to the subject at least one therapeutically effective amount of a compound of formula (I)

• or a pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof, wherein:
• R1 is H, OH, alkoxy, or oxo;
• R2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R3 is H, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
• R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, or halogen, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl;
• R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl;
• R8, R9, and R10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
• m is 0, 1, or 2;
• n is 0 or 1;
• and
• p is 0 or 1.

A kit for treating, ameliorating, or mitigating cognitive impairment in a subject, comprising at least one therapeutically effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof, and instructions for use;
• wherein:
• R1 is H, OH, alkoxy, or oxo;
• R2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R3 is H, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
• R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, or halogen, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl;
• R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl;
• R8, R9, and R10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
• m is 0, 1, or 2;
• n is 0 or 1;
• and
• p is 0 or 1.

A method of treating, ameliorating or mitigating cognitive impairment in a subject comprising administering to the subject a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof, and at least one pharmaceutically acceptable excipient;
• wherein:
• R1 is H, OH, alkoxy, or oxo;
• R2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R3 is H, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl;
• R4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
• R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, or halogen, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl;
• R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(O)NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl;
• R8, R9, and R10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
• m is 0, 1, or 2;
• n is 0 or 1;
• and
• p is 0 or 1.