Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-07-13
2002-08-20
Jarvis, William (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S356000, C514S443000, C514S448000, C514S559000, C514S475000, C514S560000
Reexamination Certificate
active
06436993
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 methods for modulating the activity of members of the steroid/thyroid hormone receptor superfamily by relieving the inhibition of hormone mediated processes caused by retinoic acid receptor, or agonists thereof. In another aspect, the present invention relates to methods for inducing hormone mediated processes.
BACKGROUND OF THE INVENTION
A central problem in eukaryotic molecular biology continues to be the elucidation of molecules and mechanisms that mediate specific gene regulation. As part of the scientific attack on this problem, a great deal of work has been done in efforts to identify ligands (i.e., exogenous inducers) which are capable of mediating specific gone regulation. Additional work has been done in efforts to identify other molecules involved in specific gene regulation.
Although much remains to be learned about the specifics of gene regulation, it is known that ligands modulate gene transcription by acting in concert with intracellular components, including intracellular receptors and discrete DNA sequences known as hormone response elements (HREs). The identification of compounds which directly or indirectly interact with intracellular receptors, and thereby affect transcription of hormone-responsive genes, would be of significant value, e.g., for therapeutic applications.
The actions of steroids, retinoids and thyroid hormones are mediated by intracellular nuclear receptors whose coordinate activity defines the physiological response (Mangelsdorf and Evans,
Cell
83:841-850 (1995)). These receptors are all structurally related and constitute a superfamily of nuclear regulatory proteins that modulate gene expression in a ligand-dependent fashion. Previous studies have demonstrated that the 9-cis retinoic acid receptor (RXR) serves as a common heterodimneric partner for thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR),
prostanoids (PRAR),
as well as numerous orphan receptors (Kliewer et al. (1992)
Nature
355:446-449).
Nuclear hormone receptor heterodimers can be classified into two distinct groups based upon their transcriptional responses to synthetic RXR ligands. So called “permissive” heterodimers such as PPAR:RXR, espond to either RXR and/or PPAR ligands and the two together have, at least, an additive effect (see, e.g., Mukherjee et al.,
Nature
386:407-10 (1997)). In contrast, so called “non-pennissive” heterodimers, such as RAR:RXR, do not respond to RXR ligands unless ligands for RAR are already present, in which case they yield an additive or synergistic response (Apfel et al.,
J Biol Chem.
270(51):30765-72.(1995); Chen et al.
PNAS
93:7567-7571 (1996)). Other non-permissive heterodimers include TR:RXR and VDR:RXR heterodimers, which also do not appear to be activated by RXR ligands. Indeed, the RXR ligand, LG100268, appears to partially antagonize the action of thyroid hormone.
This difference between permissive and non-permissive heterodimers is likely to be important for regulating the activity of naturally occurring RXR ligands (Heyman et al.,
Cell
(1992) 68:397-406; Mascrez et al.,
Development
(1998) 125(23):4691-707; Solomin et al.,
Nature
(1998) 395(6700):398-402; Fujita and Mitsuhashi,
Biochem Biophys Res Commun
(1999) 255(3):625-30)] as well as being crucial to understanding the behavior of synthetic compounds currently under development as both anti-cancer and anti-diabetic agents (see, e.g., Anzano et al.,
Cancer Research
(1994) 54:4614-4617, Gottardis et al.,
Cancer Research
(1996) 56:5566-5570, Mukheijee et al., supra). It has been also suggested that RXR can function as a homodimer (Mangelsdorf et al.,
Cell
66(3):555-61 (1991)). By competing for dimerization with RXR on response elements, the relative abundance of RAR and PPAR determines whether the RXR signaling pathway will be functional.
PPAR&agr; is a permissive member of the nuclear receptor superfamily, which includes receptors for the steroid, thyroid and retinoid hormones (see Mangelsdorf & Evans in
Cell
83:841-50 (1995)). Two other PPAR&agr;-related genes (PPAR&ggr; and PPAR&dgr;) have been identified in mammals. PPAR&ggr; is highly enriched in adipocytes, while the &ggr; isoform is ubiquitously expressed (see Schoonjans et al., in
Biochim Biophys Acta
1302:93-109 (1996)). Like other members of this receptor superfamily, all of the PPAR isoforms contain a central DNA binding domain that recognizes response elements in the promoters of their target genes (see, for example, Latruffe et al. in
Biochimie
79:81-94 (1997)). PPAR response elements (PPRE) are composed of a directly repeating core-site separated by 1 nucleotide (see Kliewer et al., in
Nature
358:771-4 (1992)). In order to recognize a PPRE, PPARs must heterodimerize with the 9-cis retinoic acid receptor (RXR).
The peroxisome proliferator activated receptors (PPARs) preferentially bind to DNA, i.e., response elements, as heterodimers with a common partner, the retinoid X (or 9-cis retinoic acid) receptor (RXR; see, for example, Kliewer et al., in
Nature
355:446-449 (1992); Leid et al, in
Cell
68:377-395 (1992); Marks et al., in EMBO J. 11:1419-1435 (1992); Zhang et al., in
Nature
355:441-446 (1992); and Issemann et al., in
Biochimie.
75:251-256 (1993). Once bound to a response element, PPARs activate transcription following binding of ligand to the C-terminal ligand binding domain thereof. Due to the key role of ligands for the activation of transcription, an intense search for the identification of ligands for members of the PPAR family has been undertaken by a number of research groups.
PPAR&agr; has been identified as a vertebrate nuclear hormone receptor which regulates genes involved in fatty acid (FA) degradation (&dgr;-and &ohgr;-oxidation; see Schoonjans et al., in
Biochim Biophys Acta
1302:93-109 (1996)). PPAR&agr; is highly expressed in the liver and was originally identified by Green and colleagues as a molecule that mediates the transcriptional effects of drugs that induce peroxisome proliferation in rodents (see Issemann & Green in
Nature
347:645-50 (1990)). Mice lacking functional PPAR&agr; are incapable of responding to these agents and fail to induce expression of a variety of genes required for the metabolism of FAs in peroxisomes, mitochondria and other cellular compartments (see Lee et al., in
Mol Cell Biol
15:3012-3022 (1995)). As a result, PPAR&agr;-deficient mice inappropriately accumulate lipid in response to pharmnacologic stimuli.
PPAR&agr; appears to regulate FA oxidation, suggesting that PPAR&agr; ligands may represent endogenous signals for FA degradation (see Schoonjans et al., supra). Fatty acids (FAs) are ubiquitous biological molecules that are utilized as metabolic fuels, as covalent regulators of signaling molecules and as essential components of cellular membranes. It is thus logical that FA levels should be closely regulated. Indeed, some of the most common medical disorders in industrialized societies (e.g., cardiovascular disease, hyperlipidemia, obesity and insulin resistance) are characterized by altered levels of FAs or their metabolites (see, for example, Durrington, in
Postgrad Med
J 69 Suppl 1, S18-25; discussion S25-9 (1993) and Reaven, in
J Intern Med Suppl
736:13-22 (1994)).
PPAR&ggr; is preferentially expressed in adipose tissue. PPAR&ggr;-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. 15-deoxy-&Dgr;
12,14
-prostaglandin J
2
(15d-J
2
) has been identified as a ligand for PPAR&ggr; (see, for example, Forman et al., in
Cell
83:803-12 (1995) and Kliewer et al., in
Cell
83:813-9 (1995)). Activation of PPAR&ggr; by 15d-J
2
or its synthetic analogs (e.g., thiazolidinediones; see Forman et al., supra) promotes differentiation of pre-adipocytes into mature, triglyceride-containing fat cells. Similarly, thiazolidinediones have been shown to increase body weight
Evans Ronald M.
Nagy Laszlo
Tontonoz Peter J.
Jarvis William
Kim Vickie
Reiter Stephen E.
The Salk Institute for Biological Studies
LandOfFree
Use of RAR antagonists as modulators of hormone mediated... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of RAR antagonists as modulators of hormone mediated..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of RAR antagonists as modulators of hormone mediated... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2882908