Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-08
2003-08-12
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S222200, C514S223200, C514S226500, C514S228800, C514S241000, C514S254080, C514S257000, C514S365000, C514S367000, C514S824000
Reexamination Certificate
active
06605627
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the modulation of nuclear receptor mediated processes. In a particular aspect, the present invention relates to the use of a specific class of compounds for the modulation of processes mediated by peroxisome proliferator activated receptor-gamma (PPAR-&ggr;).
BACKGROUND OF THE INVENTION
Peroxisome proliferators are a structurally diverse group of compounds which, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the &bgr;-oxidation cycle (Lazarow and Fujiki,
Ann. Rev. Cell Biol.
1:489-530 (1985); Vamecq and Draye,
Essays Biochem.
24:1115-225 (1989); and Nelali et al.,
Cancer Res.
48:5316-5324 (1988)). Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani,
Crit. Rev. Toxicol.
12:1-58 (1983)). Peroxisome proliferation can also be elicited by dietary or physiological factors such as a high-fat diet and cold acclimatization.
Insight into the mechanism whereby peroxisome proliferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green,
Nature
347-645-650 (1990)). This receptor, termed peroxisome proliferator activated receptor alpha (PPAR&agr;), was subsequently shown to be activated by a variety of medium and long-chain fatty acids and to stimulate expression of the genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase (enzymes required for peroxisomal &bgr;-oxidation), oxidase and hydratase-dehydrogenase (enzymes required for peroxisomal &bgr;-oxidation), as well as rabbit cytochrome P450 4A6, a fatty acid (&ohgr;-hydroxylase (Gottlicher et al.,
Proc. Natl. Acad. Sci. USA
89:4653-4657 (1992); Tugwood et al.,
EMBO J.
11:433-439 (1992); Bardot et al.,
Biochem. Biophys. Res. Comm.
192:37-45 (1993); Muerhoff et al.,
J. Biol. Chem.
267:19051-19053 (1992); and Marcus et al.,
Proc. Natl. Acad. Sci. USA
90(12):5723-5727 (1993).
The above-noted references suggest a physiological role for PPAR&agr; in the regulation of lipid metabolism. PPAR&agr; activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), as a heterodimer with the retinoid X receptor. The retinoid X receptor is activated by 9-cis retinoic acid (see Kliewer et al.,
Nature
358:771-774 (1992), Gearing et al.,
Proc. Natl. Acad. Sci. USA
90:1440-1444 (1993), Keller et al.,
Proc. Natl. Acad. Sci. USA
90:2160-2164 (1993), Heyman et al.,
Cell
68:397-406 (1992), and Levin et al.,
Nature
355:359-361 (1992)). Since the PPAR&agr;-RXR complex can be activated by peroxisome proliferators and/or 9-cis retinoic acid, the retinoid and fatty acid signaling pathways are seen to converge in modulating lipid metabolism.
Since the discovery of PPAR&agr;, additional isoforms of PPAR have been identified, e.g., PPAR&agr;, PPAR&ggr; and PPAR&dgr;, which are spatially differentially expressed. Because there are several isoforms of PPAR, it would be desirable to identify compounds which are capable of selectively interacting with only one of the PPAR isoforms. Such compounds would find a wide variety of uses, such as, for example, in the prevention of obesity, for the treatment of diabetes, and the like.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have identified a class of compounds which are capable of modulating processes mediated by peroxisome proliferator activated receptor-gamma (PPAR-&ggr;). The identification of such compounds makes possible intervention in PPAR-&ggr; mediated pathways.
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Evans Ronald M.
Forman Barry M.
Foley & Lardner
Reiter Stephen E.
The Salk Insitute for Biological Studies
Weddington Kevin E.
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