Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-04
2001-09-11
Venkat, Jyothsna (Department: 1627)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S193000, C546S194000, C546S195000, C546S196000, C546S197000, C546S198000, C546S199000, C546S200000, C546S201000, C546S202000, C546S203000, C546S204000, C546S205000, C546S206000, C546S207000, C546S208000, C514S252010, C514S325000, C514S326000, C514S424000, C514S426000, C530S345000, C530S389100, C530S402000, C530S807000, C549S016000, C549S388000, C564S172000, C564S174000
Reexamination Certificate
active
06288234
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that inhibit microsomal triglyceride transferase protein (MTP) and to pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in preventing and treating various disorders associated with hyperlipidemia and related disorders, such as atherosclerosis.
References
The following publications are cited in this application as superscript numbers:
1
J. R. Wetterau et al.,
Biochim. Biophys. Acta
1997, 1345, 136-150.
2
D. A. Gordon et al.,
Trends Cell Biol
. 1995, 5, 317-321.
3
Robbins
Pathological Basis of Disease
, 5
th
Edition (1994), pp. 473-484.
4
S. L. Ohringer et al.,
Acta Crystallogr., Sect. D: Biol. Crystallogr
. 1996, D52(1), 224-225.
5
J. R. Wetterau et al.,
J. Biol. Chem
. 1990, 265, 9800-9807.
6
J. R. Wetterau et al.,
Biochemistry
1991, 30, 4406-4412.
7
C. C. Shoulders et al.,
J. Hum. Mol. Genet
. 1993, 2, 2109-2116.
8
R. Raag et al.,
J. Mol. Biol
. 1988, 200, 553-569.
9
P. A. Timmins et al.,
Science
1992, 257, 652-655.
10
A. Atzel et al.,
Biochemistry
1993, 32, 10444-10450.
11
A. Atzel et al.,
Biochemistry
1994, 33, 15382-15388.
12
H. Jamil et al.,
J. Biol. Chem
. 1995, 270, 6549-6554.
13
H. Jamil et al.,
Proc. Natl. Acad. Sci. U.S.A
. 1996, 93, 11991-11995.
14
J. P. Kane et al.,
The Metabolic Basis of Inherited Disease
, Scriver et al., Eds.; McGraw-Hill, N.Y., Ed. 7, 1995, pp. 1853-1885.
15
M. F. Linton et al.,
J. Lipid Res
. 1993, 34, 521-541.
16
U.S. Pat. No. 5,712,279, issued Jan. 27, 1998 to Biller et al.
17
U.S. Pat. No. 5,739,135, issued Apr. 14, 1998 to Biller et al.
18
U.S. Pat. No. 5,760,246, issued Jun. 2, 1998 to Biller et al.
19
U.S. Pat. No. 5,827,875, issued Oct. 27, 1998 to Dickson Jr. et al.
20
U.S. Statutory Invention Registration No. H1729, published May 5, 1998 by Biller et al.
21
WO 96/40640, published Dec. 19, 1996.
22
WO 97/26240, published Jul. 24, 1997.
23
WO 97/43255, published Nov. 20, 1997.
24
WO 98/03069, published Jan. 29, 1998.
25
WO 98/03174, published Jan. 29, 1998.
26
WO 98/23593, published Jun. 4, 1998.
27
WO 98/27979, published Jul. 2, 1998.
28
WO 98/31225, published Jul. 23, 1998.
29
WO 98/31366, published Jul. 23, 1998.
30
WO 98/31367, published Jul. 23, 1998.
31
EP 0 643 057 Al, published Mar. 15, 1995.
32
M. Haghpassand et al.,
J. Lipid Res
. 1996, 37, 1468-1480.
33
F. Benoist et al.,
Eur. J. Biochem
. 1996, 240, 713-720.
34
J. R. Wetterau et al.,
Science
1998, 282, 751-754.
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.
2. State of the Art
Microsomal triglyceride transferase protein (MTP) is a lipid transfer protein which mediates the transport of lipids, such as triglycerides, cholesterol esters, and phosphatidylcholine, between membranes.
1,2
Accordingly, MTP is believed to play a role in the assembly of lipoproteins and related biomolecules. In this regard, MTP has been implicated as a probable agent in the assembly of apolipoprotein B (Apo B)-containing lipoproteins which are known to contribute to the formation of atherosclerotic lesions. Thus, effective inhibitors of MTP would be useful in preventing the onset and progression of atherosclerosis, including myocardial infarction, stroke, peripheral vascular disease and the like, which accounts for one-half of deaths in the United States.
3
MTP was originally isolated from the microsomal fraction of bovine liver and has subsequently been found within the lumen of microsomes isolated from both the liver and intestine.
1
Since its initial isolation, MTP has been extensively characterized.
4,5,6
MTP is a soluble, heterodimeric protein composed of 58 and 97 kDa subunits, both of which are required for activity. The protein is localized within the lumen of the endoplasmic reticulum. The 58 kDa subunit is identical to protein disulfide isomerase (PDI), though the complex exhibits no PDI activity and isolated PDI does not exhibit MTP activity. The noncovalent MTP heterodimer does not display significant dissociation/reassociation and is either asymmetric and/or highly hydrated. The unique 97 kDa subunit bears homology to other lipid-transporting proteins, including the lipovitillin-phosvitin complex (LPC) and, to a lesser extent, plasma cholesteryl ester transfer protein (CETP).
7
Structural characterization of LPC reveals that it comprises a large cavity that complexes multiple copies of phospholipid.
8,9
Kinetic analysis of the MTP-mediated lipid transport processes have revealed ping pong bi bi kinetics which is consistent with a mechanism of action in which MTP binds and shuttles lipid molecules between membranes.
10
This suggests that stable MTP-lipid complexes are formed during the transfer process, which is further supported by the observation that incubation of MTP with donor vesicles containing a variety of radio-labeled lipids followed by re-isolation affords MTP containing up to three molecules of lipid.
11,12
The ability of lipid molecules to occupy distinct binding sites on MTP is suggested by the observation of biphasic kinetics for transfer of phosphatidyl choline, which binds with a 2:1 stoichiometry to the enzyme.
12
Moreover, an MTP inhibitor has been hown to fully ablate the MTP-mediated transfer of triglycerides and cholesterol sters but not that of phosphatidyl choline.
13
The ability of MTP inhibitors to prevent the onset and progression of therosclerosis and related disorders is supported by the observation that utations in MTP are the only known bases for abetalipoproteinemia, an autosomal recessive disorder characterized by the virtual absence of apoB-containing plasma lipoproteins.
1,2,14
Abetalipoproteinemia sub atherosclerosis, but they suffer from a variety of side effects as a result of the extreme nature of their condition. This suggests that non-complete inhibition of MTP would be requisite in an agent designed for human therapy. In this regard, hypobetalipoproteinemia is a relevant model for MTP inhibition. This condition is displayed by individuals who are heterozygous for mutations in apolipoproteinB.
15
These subjects have levels of apoB-containing lipoproteins half that of normal subjects and, as a result, they enjoy extended lifespans.
Inhibitors of MTP have been described in the patent and technical literature. See, by way of example, U.S. Pat. No. 5,712,279;
16
U.S. Pat. No. 5,739,135;
17
U.S. Pat. No. 5,760,246;
18
U.S. Pat. No. 5,827,875;
19
U.S. Statutory Invention Registration No. H1729;
20
WO 96/40640;
21
WO 97/26240;
22
WO 97/43255;
23
WO 98/03069;
24
WO 98/03174;
25
WO 98/23593;
26
WO 98/27979;
27
WO 98/31225;
28
WO 98/31366;
29
WO 98/31367;
3
EP 0 643 057 A1;
31
M. Haghpassand et al.;
32
F. Benoist et al.;
33
and J. R. Wetterau et al.
34
Notwithstanding such inhibitors, a need exists for effective MTP inhibitors having improved biological and/or therapeutic effects.
It has now been discovered that MTP inhibitors having surprising and unexpected properties can be prepared by linking from 2 to 10 ligands capable of binding to MTP to one or more linkers. The chemical structure of one known inhibitor of MTP, i.e. BMS-201038, is illustrated in
FIG. 1A.
16,34
Without being limited to theory, a potential complex of this compound with MTP is illustrated in FIG.
1
B. Based on the distinct multiple binding sites believed to be present in MTP, various multibinding compounds are illustrated in FIG.
1
B. 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 microsomal triglyceride transferase protein (MTP). The multibinding compounds of this invention a
Advanced Medicine, Inc.
Burns Doane Swecker & Mathis L.L.P.
Garcia Maurie E.
Venkat Jyothsna
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