Compounds, compositions and methods useful for cholesterol mobilization
The invention relates to classes of pharmaceutically-active heterocyclic compounds and pharmaceutically acceptable salts, and hydrates thereof, and compositions comprising the same. The invention also relates to methods for treating or preventing a disease or disorder, which comprises administering a therapeutically or prophylactically effective amount a compound described herein.
1. A compound of Formula (VII):
or a pharmaceutically acceptable salt thereof, wherein
each of R 1a , R 1b , and R 1c is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ;
each X is independently CHR 10 , S, O, or NR 9 ;
each R 9 is independently H, hydrocarbyl, aryl, aralkyl, heteroaryl, heterocyclyl, —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), or —SO 2 NH 2 ;
each R 10 is independently —H, —OH, —NH 2 , —NH(alkyl), —N(alkyl)(alkyl), hydrocarbyl, O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralykl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), or —SO 2 NH 2 ; and
m is an integer from 0-3.
2. The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
3. A composition comprising an effective amount of a compound or pharmaceutically acceptable salt of a compound of claim 1 or 2 and a pharmaceutically acceptable vehicle or carrier.
4. The composition of claim 3 , wherein the composition is formulated for oral administration.
5. The composition of claim 3 , wherein the composition is in the form of a tablet or capsule.
6. The composition of claim 3 , wherein the compound or salt thereof is present in an amount of about 1 mg to about 1,000 mg.
7. A method for treating a disorder of lipoprotein metabolism, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
8. The method of claim 7 , wherein the disorder of lipoprotein metabolism is dyslipidemia, dyslipoproteinemia, lipoprotein overproduction or deficiency, elevation of total cholesterol, elevation of low density lipoprotein concentration, elevation of triglyceride concentration, lipid elimination in bile, metabolic disorder, phospholipid elimination in bile, oxysterol elimination in bile, or peroxisome proliferator activated receptor-associated disorder.
9. A method of treating a disorder of glucose metabolism, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
10. The method of claim 9 , wherein the disorder of glucose metabolism is insulin resistance, impaired glucose tolerance, impaired fasting glucose levels in blood, diabetes mellitus, lipodystrophy, central obesity, peripheral lipoatrophy, diabetic nephropathy, diabetic retinopathy, renal disease, or septicemia.
11. A method of treating a cardiovascular disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
12. The method of claim 11 , wherein the cardiovascular disorder or related vascular disorders is hypertension, coronary artery disease, myocardial infarction, arrhythmia, atrial fibrillation, heart valve disease, heart failure, cardiomyopathy, or pericarditis.
13. The method of claim 11 , wherein the method provides relief from at least one symptom of the cardiovascular disorder.
14. The method of claim 13 , wherein the symptom is impotence.
15. A method of treating inflammation, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
16. A method of treating ischemic necrosis, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
17. A method of treating colon cancer, lung cancer, breast cancer, or skin cancer, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
18. A method of treating a thrombotic disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
19. A method of treating Alzheimer's Disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
20. A method of treating Parkinson's Disease, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
21. A method of treating pancreatitis, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
22. A method of treating abnormal bile production, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
23. A method of monitoring the progress of therapy for a cardiovascular disorder in a subject, the method comprising:
a. determining the level of free cholesterol in the high-density lipoprotein in the blood of the subject;
b. administering to the subject a compound of claim 1 or 2 ;
c. monitoring the level of free cholesterol in the blood of the subject for a period of time after administration of the compound; and
d. evaluating the level of improvement in the subject based on a comparison of the results of steps a. and c.
24. The method of claim 23 , wherein the cardiovascular disorder is reverse cholesterol transport from artery to liver or cholesterol elimination in bile acids.
25. A method of determining the level of P2Y13 activity in a subject, the method comprising:
a. determining the level of free cholesterol in the high-density lipoprotein in the blood of the subject;
b. administering to the subject a compound of claim 1 or 2 ;
c. monitoring the level of free cholesterol in the blood of the subject for a period of time after administration of the compound; and
d. evaluating the level of P2Y13 activity in the subject based on a comparison of the results of steps a. and c.
26. A method for treating a hepatic steatosis, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 1 or 2 .
27. The method of claim 26 , wherein the hepatic steatosis is alcoholic hepatic steatosis or non-alcoholic hepatic steatosis.