METHODS FOR AMELIORATING COGNITIVE IMPAIRMENT USING BILE ACID DERIVATIVES
The disclosure relates to methods of using bile acid derivatives for the treatment and/or prevention of cognitive disorders, diseases, or conditions.
1 . A method of ameliorating, mitigating, treating, or preventing cognitive impairment in 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:
R 1 is H, OH, alkoxy, or oxo;
R 2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 3 is H, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , or halogen, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, 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;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 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 R 9 and R 10 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.
2 . The method of claim 1 , wherein the compound of formula (I) is a compound of formula (A):
or pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof.
3 . The method of claim 2 , wherein the compound of formula (I) is a compound of formula (A).
4 . The method of claim 1 , wherein the compound of formula (I) is a compound of formula (B):
or pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof.
5 . The method of claim 4 , wherein the compound of formula (I) is a compound of formula (B).
6 . The method of claim 1 , wherein the compound of formula (I) is a compound of formula (C):
or pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof.
7 . The method of claim 6 , wherein the compound of formula (I) is a compound of formula (C).
8 . The method of claim 1 , wherein the compound of formula (I) is a compound of formula (D):
or pharmaceutically acceptable salt, ester, solvate, or amino acid conjugate thereof.
9 . The method of claim 8 , wherein the compound of formula (I) is a compound of formula (D).
10 . The method of claim 1 , wherein the cognitive impairment is associated with a neurological disease.
11 . The method of claim 10 , wherein the neurological disease is Parkinson's disease.
12 . The method of claim 10 , wherein the neurological disease is Parkinson's disease dementia.
13 . The method of claim 10 , wherein the neurological disease is mild cognitive impairment in Parkinson's disease dementia (PD-MCI).
14 . The method of claim 1 , wherein the effective amount of the compound of formula (I) is between about 1 mg and about 50 mg.
15 . The method of claim 14 , wherein the effective amount of the compound of formula (I) is between about 1 mg and about 25 mg.
16 . The method of claim 14 , wherein the effective amount of the compound of formula (I) is about 25 mg.
17 . The method of claim 1 , wherein the effective amount of the compound of formula (I) is administered about every day, about every two days, about every three days, or about every week.
18 . The method of claim 17 , wherein the effective amount of the compound of formula (I) is administered daily.
19 . 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:
R 1 is H, OH, alkoxy, or oxo;
R 2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 3 is H, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , or halogen, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, 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;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 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 R 9 and R 10 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.
20 . 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:
R 1 is H, OH, alkoxy, or oxo;
R 2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 3 is H, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , or halogen, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, 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;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 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 R 9 and R 10 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.
21 - 23 . (canceled)
24 . 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:
R 1 is H, OH, alkoxy, or oxo;
R 2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 3 is H, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , or halogen, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, 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;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 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 R 9 and R 10 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.
25 . 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:
R 1 is H, OH, alkoxy, or oxo;
R 2 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 3 is H, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , or halogen, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, 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;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 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 R 9 and R 10 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.