LXR modulators

Details LXR modulators LXR modulators

2000-03-14

2001-11-13

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S585000, C514S596000, C514S447000, C514S448000, C514S352000, C514S354000, C514S371000, C514S365000, C564S084000, C564S092000, C564S052000, C564S053000, C564S055000, C564S026000, C549S069000, C549S072000, C546S308000, C546S310000, C548S196000, C548S200000

Reexamination Certificate

active

06316503

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds and methods useful for the modulation of LXR. In view of the activity of LXR in the control of cholesterol homeostasis, the compounds described herein are useful for lowering plasma cholesterol levels.
BACKGROUND
Cholesterol is used for the synthesis of bile acids in the liver, the manufacture and repair of cell membranes, and the synthesis of steroid hormones. There are both exogenous and endogenous sources of cholesterol. The average American consumes about 450 mg of cholesterol each day and produces an additional 500 to 1,000 mg in the liver and other tissues. Another source is the 500 to 1,000 mg of biliary cholesterol that is secreted into the intestine daily; about 50 percent is reabsorbed (enterohepatic circulation). Excess accumulation of cholesterol in the arterial walls can result in atherosclerosis, which is characterized by plaque formation. The plaques inhibit blood flow, promote clot formation and can ultimately cause heart attacks, stroke and claudication. Development of therapeutic agents for the treatment of atherosclerosis and other diseases associated with cholesterol metabolism has been focused on achieving a more complete understanding of the biochemical pathways involved. Most recently, liver X receptors (LXRs) were identified as key components in cholesterol homeostasis.
The LXRs were first identified as orphan members of the nuclear receptor superfamily whose ligands and functions were unknown. Two LXR proteins (&agr; and &bgr;) are known to exist in mammals. The expression of LXR&agr; is restricted, with the highest levels being found in the liver, and lower levels found in kidney, intestine, spleen, and adrenals (see Willy, et al.,
Genes Dev
. 9(9):1033-45 (1995)). LXR&bgr; is rather ubiquitous, being found in nearly all tissues examined. Recent studies on the LXRs indicate that they are activated by certain naturally occurring, oxidized derivatives of cholesterol, including 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol and 24,25(S)-epoxycholesterol (see Lehmann, et al.,
J. Biol. Chem
. 272(6):3137-3140 (1997)). The expression pattern of LXRs and their oxysterol ligands provided the first hint that these receptors may play a role in cholesterol metabolism (see Janowski, et al.,
Nature
383:728-731 (1996)).
As noted above, cholesterol metabolism in mammals occurs via conversion into steroid hormones or bile acids. The role of LXRs in cholesterol homeostasis was first postulated to involve the pathway of bile acid synthesis, in which cholesterol 7&agr;-hydroxylase (CYP7A) operates in a rate-limiting manner. Support for this proposal was provided when additional experiments found that the CYP7A promoter contained a functional LXR response element that could be activated by RXR/LXR heterodimers in an oxysterol- and retinoid-dependent manner. Confirmation of LXR function as a transcriptional control point in cholesterol metabolism was made using knockout mice, particularly those lacking the oxysterol receptor LXR&agr; (see Peet, et al.,
Cell
93:693-704 (1998)).
Mice lacking the receptor LXR&agr; (e.g., knockout or (−/−) mice) lost their ability to respond normally to increases in dietary cholesterol and were unable to tolerate any cholesterol in excess of that synthesized de novo. LXR&agr; (−/−) mice did not induce transcription of the gene encoding CYP7A when fed diets containing additional cholesterol. This resulted in an accumulation of large amounts of cholesterol and impaired hepatic function in the livers of LXR&agr; (−/−) mice. These results further established the role of LXR&agr; as the essential regulatory component of cholesterol homeostasis. LXR&agr; is also believed to be involved in fatty acid synthesis. Accordingly, regulation of LXR&agr; (e.g., use of LXR&agr; agonist or antagonists) could provide treatment for a variety of lipid disorders including obesity and diabetes.
In view of the importance of LXRs, and particularly LXR&agr;s to the delicate balance of cholesterol metabolism and fatty acid biosynthesis, we describe modulators of LXRs which are useful as therapeutic agents or diagnostic agents for the treatment of disorders associated with bile acid and cholesterol metabolism, including cholesterol gallstones, atherosclerosis, lipid storage diseases, obesity, and diabetes. The agents described herein are also useful for disease states associated with serum hypercholesterolemia, such as coronary heart disease.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compositions for modulation of LXR&agr; function in a cell. The compositions typically comprise a pharmaceutically acceptable excipient and a compound having the formula:
wherein Ar represents an aryl group; R
1
is —OH, —O—(C
1
-C
7
)alkyl, —OC(O)—(C
1
-C
7
)alkyl, —O—(C
1
-C
7
)heteroalkyl, —OC(O)—(C
1
-C
7
)heteroalkyl, —CO
2
H, —NH
2
, —NH(C
1
-C
7
)alkyl, —N((C
1
-C
7
)alkyl)
2
or —NH—S(O)
2
—(C
1
-C
5
)alkyl; R
2
is (C
1
-C
7
)alkyl, (C
1
-C
7
)heteroalkyl, aryl and aryl(C
1
-C
7
)alkyl; X
1
, X
2
, X
3
, X
4
, X
5
and X
6
are each independently H, (C
1
-C
5
)alkyl, (C
1
-C
5
)heteroalkyl, F or Cl, with the proviso that no more than three of X
1
through X
6
are H, (C
1
-C
5
)alkyl or (C
1
-C
5
)heteroalkyl; and Y is —N(R
12
)S(O)
m
—, —N(R
12
)S(O)
m
N(R
13
)—, —N(R
12
)C(O)—, —N(R
12
)C(O)N(R
13
)—, —N(R
12
)C(S)— or —N(R
12
)C(O)O—, wherein R
12
and R
13
are each independently hydrogen, (C
1
-C
7
)alkyl, (C
1
-C
7
)heteroalkyl, aryl and aryl(C
1
-C
7
)alkyl, and optionally when Y is —N(R
12
)S(O)
m
— or —N(R
12
)S(O)
m
N(R
13
)—, R
12
forms a five-, six- or seven-membered ring fused to Ar or to R
2
through covalent attachment to Ar or R
2
, respectively. In the above Y groups, the subscript m is an integer of from 1 to 2.
Preferred compositions are those in which the compound above binds to the ligand binding domain of LXR&agr; with an affinity of at least 1 micromolar.
A number of compounds that are useful in the above-described compositions are novel. Accordingly, the present invention further provides compounds of the above formula, with the proviso that when R
1
is OH, and —Y—R
2
is —N(R
12
)S(O)
m
R
2
or —N(R
12
)C(O)N(R
13
)—R
2
and is attached to a position para to the quaternary carbon attached to Ar, and when R
2
is phenyl, benzyl or benzoyl, then i) at least one of R
12
or R
13
is other than hydrogen and contains an electron-withdrawing substituent, or ii) R
2
is substituted with a moiety other than amino, acetarnido, di(C
1
-C
7
)alkylamino, (C
1
-C
7
)alkylamino, halogen, hydroxy, nitro, or (C
1
-C
7
)alkyl, or iii) the benzene ring portion of R
2
is trisubstituted in addition to the Y group.
In yet another aspect, the present invention provides methods for modulating LXR in a cell by administering to or contacting the cell with a composition containing a compound of Formula I above.
In still another aspect, the present invention provides methods for treating LXR-responsive diseases by administering to a subject in need of such treatment a composition containing a compound of Formula I. These methods are particularly useful for the treatment of pathology such as hypercholesterolemia, atherosclerosis, and hyperlipoproteinemia. In certain embodiments, the compound can be administered to the subject in combination with an additional anti-hypercholesterolemic agent, for example, bile acid sequestrants, nicotinic acid, fibric acid derivatives or HMG CoA reductase inhibitors.
The present compounds can exert their effects either systemically (the compounds permeate the relevant tissues, such as liver, upon entrance into the bloodstream) or locally (for example, by modulating LXR function of intestinal epithelial cells following oral administration, without necessitating the compounds' entrance into the bloodstream). In some disease states, some preferred compounds will be those with good systemic distribution, while, in other instances, preferred compounds will be those that can work locally on the intestinal tra

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