Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
2001-07-19
2004-01-13
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Reexamination Certificate
active
06677298
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for treating obesity, insulin resistance and dyslipidemia in mammals including humans through inhibition of PPAR&dgr;(&bgr;). This invention also relates to methods of screening for chemical entities that act to regulate PPAR&dgr;(&bgr;) activity. The invention further relates to a method of treatment of obese, insulin resistant and hyperlipidemic patients with one or more combinations of a PPAR&dgr;(&bgr;) antagonist, an anti-diabetic agent and a lipid-lowering agent.
BACKGROUND OF THE INVENTION
Obesity is a common clinical problem in most developed nations and is also rapidly becoming a major health concern in developing nations. Overweight individuals frequently suffer from several metabolic disorders such as insulin resistance, type 2 diabetes and dyslipidemia. These individuals also frequently suffer from hypertension, increased risk for cardiovascular diseases such as atherosclerosis and coronary heart disease, and osteoarthritis of the joints.
In mammals, including humans, adipocytes (fat cells) store excess energy in the form of triglycerides at times of nutritional excess (see Lowell,
Cell,
99:239-242, 1999). During starvation, triglycerides are degraded to fatty acids in adipocytes in order to supplement nutritional and energy requirements. However, excess adiposity achieved either through recruitment of progenitor cells (pre-adipocytes) to become adipocytes (differentiation) and/or through expansion of the pre-existing adipocytes (hypertrophy), is associated with obesity (see Lowell,
Cell,
99:239-242, 1999). Hypertrophied adipocytes have been demonstrated to produce excessive amounts of cytokines such as TNF&agr;(which in turn act to reduce insulin receptor activity and/or response to insulin signaling in skeletal muscle and adipocytes, two major glucose utilizing tissues (see Hotamisligil, et al.,
Science,
259:87-90, 1993; Lowell,
Cell,
99:239-242, 1999). This results in insulin resistance, reduced glucose uptake, and in some individuals type 2 diabetes. Obese individuals with insulin resistance and type 2 diabetes also frequently suffer from hyperlipidemia, atherosclerosis and cardiovascular diseases (see Rosenbaum et al.,
New. Eng. J. Med.
337:396-407, 1997).
Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor family of ligand regulated transcription factors (see Willson, et al.,
J. Med. Chem.,
43:527-550, 2000). Three PPAR isoforms, PPAR&agr;, PPAR&ggr; and PPAR&dgr;, have been isolated from various mammalian species including humans. These receptors, as a class, form obligate heterodimers with their binding partner RXR&agr;, and are activated by diet derived long chain fatty acids, fatty acid metabolites and/or by synthetic agents (see Willson, et al.,
J. Med. Chem.,
43:527-550, 2000). PPAR&agr; regulates genes in the fatty acid synthesis, fatty acid oxidation and lipid metabolism pathways (see Issenman and Green,
Nature,
347: 645-649, 1990; Torra et al.,
Current Opinion in Lipidology,
10:151-159, 1999). The marketed PPAR&agr; agonists, such as fenofibrate and gemfibrozil, lower plasma lipids in mammals including humans (see Balfour et al., Drugs. 40:260-290, 1990; Frick et al.,
New Eng. J. Med.,
317:1237-1245; Rubins et al.,
New Eng. J. Med.,
341:410-418, 1999). PPAR&ggr; has been demonstrated to regulate pre-adipocyte recruitment and differentiation into mature adipocytes. Activators of PPAR&ggr; promote lipid storage in adipocytes and act as insulin sensitizing anti-diabetic agents (see Lehmann et al.,
J. Biol. Chem.,
270:12953-12956, 1995; Nolan et al.
New. Eng. J. Med.,
331:1188-1193; Inzucchi et al.,
New Eng. J. Med.,
338:867-872, 1998). The role of the relatively more ubiquitously expressed PPAR&dgr;(also known as PPAR&bgr;, herein referred to as PPAR&dgr;(&bgr;)) isoform has been unclear although it is known that: (1) PPAR&dgr;(&bgr;) is present in pre- and mature adipocytes, and (2) it is activated by fatty acids and fatty acid metabolites (see Zhang et al.,
Mol. Endocrinology,
10:1457-1466, 1996; Berger et al.
J. Biol. Chem.,
274:6718-6725, 1999; Bastie et al.,
J. Biol. Chem.,
274:21920-21925, 1999).
SUMMARY OF THE INVENTION
Accumulation of excess adipocyte tissue either through recruitment of progenitor cells to become adipocytes and/or expansion of the pre-existing adipocytes is frequently associated with obesity. Although expressed in pre- and mature adipocytes and activated by fatty acids and fatty acid metabolites, the role of PPAR&dgr;(&bgr;) in adipocyte function, adipocyte hypertrophy and or development of obesity has not been clear. The present invention demonstrates for the first time a role for PPAR&dgr;(&bgr;) in the development of diet-induced obesity.
Accordingly, one object of the present invention is to provide a method for treating obesity in a mammal, including human, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound or combination of compounds that inhibits or modulates PPAR&dgr;(&bgr;) activity.
Another object of the present invention provides a method for treating obesity, insulin resistance and dyslipidemia in a mammal, including human, comprising administering to the mammal in need of such treatment a therapeutically effective any combination of two or more of the following compounds: a compound or combination of compounds that inhibit PPAR&dgr;(&bgr;) activity, an anti-diabetic compound, and a lipid-lowering agent.
Another object of the present invention provides a method for treating osteoarthritis in a mammal, including human, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound or combination of compounds that inhibits or modulates PPAR&dgr;(&bgr;) activity.
Another object of the present invention provides a method for screening for compounds that inhibits or regulate PPAR&dgr;(&bgr;) activity.
Another object of the present invention provides a pharmaceutical composition for the treatment of obesity, insulin resistance and/or dyslipidemia, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or combination of compounds that inhibit or regulate PPAR&dgr;(&bgr;) activity.
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Bristol--Myers Squibb Company
Buchholz Briana C.
Carlson Karen Cochrane
Klein Christopher A.
Snedden Sheridan
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