Multibinding inhibitors of HMG-CoA reductase

Details Multibinding inhibitors of HMG-CoA reductase Multibinding inhibitors of HMG-CoA reductase

1999-06-04

2002-03-12

Venkat, Jyothsna (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C435S007100, C435S007200, C436S501000, C436S518000, C514S099000, C514S414000, C514S427000, C514S428000, C514S460000, C546S255000, C546S267000, C548S517000, C548S562000, C548S577000, C548S400000, C548S414000, C548S494000, C549S006000, C549S060000, C549S216000, C549S264000, C549S292000

Reexamination Certificate

active

06355810

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis, and to pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of hypercholesterolemia, hyperlipidemia, atherosclerosis and the like.
2. References
The following publications are cited in this application as superscript numbers:
1
A. Endo et al.,
FEBS Letters
1976, 72, 323-326.
2
P. Louis-Flamberg et al.,
Biochemistry
1990, 29, 4115-4120.
3
H. Pang et al.,
Pharmacotherapy
1997, 17, 1157-1177.
4
H. Bischoff et al.,
Atherosclerosis
1997, 135, 119-130.
5
C. B. Blum,
J. Cardiol
1994, 73, 3D-11D.
6
J. D. Bergstrom et al.,
Biochim. Biophys. Acta
1998, 1389, 213-221.
7
C. E. Nakamura et al.,
Biochemistry
1985, 24, 1364-1376.
8
U.S. Pat. No. 4,963,538, issued Oct. 16, 1990 to Duggan et al.
9
EP Publication No. 0 251 625 B1, published May 29, 1991.
10
U.S. Pat. No. 4,739,073, issued Apr. 19, 1988 to Kathawala.
11
B. D. Roth et al.,
J. Med. Chem
. 1990, 34, 357-366.
12
C. Chan et al.,
J. Med. Chem
. 1993, 36, 3646-3657.
13
G. Beck et al.,
J. Med. Chem
. 1990, 33, 52-60.
14
J. Robl et al.,
J. Med. Chem
. 1991, 34, 2804-2815.
15
C. M. Lawrence et al.,
Science
1995, 268, 1758-1762.
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Over the past 15 years, a number of new drugs collectively known as statins or vastatins have been introduced to reduce serum LDL cholesterol levels (representative examples of these drugs are shown in FIG.
1
). High LDL cholesterol levels have been shown to be an important risk factor in the development of arteriosclerosis and ischaernic heart disease. The statins have been found to lower serum LDL cholesterol levels in a dose dependent manner. Additionally, these drugs lower serum triglyceride levels; another risk factor for heart disease.
The statins lower serum LDL cholesterol levels by competitive inhibition of 3-hydroxyl-3-methylglutaryl-Coenzyme A reductase (HMG-COA reductase), an enzyme involved in the biosynthesis of cholesterol.
1-4
The two-step reduction of HMG-CoA is illustrated in FIG.
2
. The statins, such as simvastatin, appear to be mimics or analogs of intermediate C shown in FIG.
2
. By binding tightly to the active site of the enzyme, the statins block the reduction of HMG-CoA, a step necessary in the biosynthesis of cholesterol. This inhibition of cholesterol biosynthesis by the statins results in a decrease in the production and secretion of LDL cholesterol. In addition, the upregulation of LDL receptors, especially in the liver, leads to the removal of LDLs from the serum. Thus, by reducing the production of LDL cholesterol and by causing LDL cholesterol to be removed from the serum, the statins effectively reduce overall serum LDL cholesterol levels.
Two-thirds of the total cholesterol found in the body is of endogenous origin. The major site of cholesterol biosynthesis is in the liver. Such liver-derived cholesterol is the main cause of the development of hyper-cholesterolaemia. In contrast, cholesterol production in non-hepatic cells is needed for normal cell function. Therefore, selective inhibition of HMG-CoA reductase in the liver is an important requirement for HMG-COA reductase inhibitors. In this regard, the statins typically have high oral availability and high hepatic extraction during their first pass through the liver.
5
Even though the current HMG-CoA reductase inhibitors are quite potent, (i.e., having IC
50
's in the range of about 1 nanomolar), a need exists for even more potent and longer lasting HMG-CoA reductase inhibitors. Tighter binding inhibitors would decrease the amount of drug that escapes from the liver and this, in turn, would decrease adverse side effects. Additionally, a longer plasma half-life appears to be associated with maximum cholesterol lowering.
6
Thus, increasing the duration of effect of the inhibitor is expected to result in even lower serum cholesterol levels.
It has now been discovered that HMG-CoA reductase inhibitors having surprising and unexpected properties can be prepared by linking from 2 to 10 ligands capable of binding to HMG-CoA reductase to one or more linkers. Such multibinding compounds provide greater biological and/or therapeutic effects than the aggregate of the unlinked ligands due to their multibinding properties.
SUMMARY OF THE INVENTION
This invention is directed to novel multibinding compounds (agents) that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The multibinding compounds of this invention are useful in the treatment and prevention of hypercholesterolemia, hyperlipidemia, atherosclerosis and the like.
Accordingly, in one of its composition aspects, this invention provides a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands independently comprises a moiety capable of binding to 3-hydroxy-3-methylglutaryl coenzyme A reductase and further wherein the distance between ligands is at least 10 Å; and pharmaceutically acceptable salts thereof.
In another of its composition aspects, this invention provides a multibinding compound of formula I:
(L)
p
(X)
q
  I
wherein each L is independently a ligand comprising a moiety capable of binding to 3-hydroxy-3-methylglutaryl coenzyme A reductase; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and further wherein the distance between ligands is at least 10 Å; and pharmaceutically acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
Preferably, each ligand, L, in the multibinding compound of formula I is independently selected from the group consisting of:
(a) a compound of formula IA:
 wherein
A
1
is selected from the group consisting of:
where IV is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically-acceptable cation;
R
1
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, heterocyclic, amino, substituted amino, thioalkoxy, substituted thioalkoxy and thioaryloxy;
R
2
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—OR
d
where R
d
is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker; or R
2
together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
R
3
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—OR
d
where R
d
is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker; or R
3
together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
R
4
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, carboxyl, hydroxy, keto, thioalkoxy, thioaryloxy, ═N—OR
d
where R
d
is hydrogen or alkyl, and a covalent bond attaching the ligand to a linker; or R
4
together with the carbon atom to which it is attached represents a spiro-attached cycloalkyl group;
R
5
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, aminoacyl, aminoacyloxy, aryloxy, c

Affiliated with

Also associated with

Rating

Multibinding inhibitors of HMG-CoA reductase does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Multibinding inhibitors of HMG-CoA reductase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Multibinding inhibitors of HMG-CoA reductase will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2872242