Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-19
2003-11-25
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S558000, C514S559000, C514S560000, C514S561000, C514S562000, C514S563000, C514S564000, C514S565000, C514S566000, C514S567000, C514S568000, C514S569000, C514S570000, C514S571000, C514S572000, C514S463000, C514S467000, C514S725000
Reexamination Certificate
active
06653322
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the fields of retinoid receptor biology and mammalian disease therapeutics. Specifically, the present invention provides compositions and methods for treating an animal, preferably a human, suffering from or predisposed to a physical disorder, by administering to the animal an effective amount of a composition comprising at least one RAR antagonist, preferably an RAR&agr; antagonist, and at least one RXR agonist.
2. Related Art
Retinoids
A number of studies have demonstrated that retinoids (vitamin A derivatives) are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, See Spom et al.,
The Retinoids
, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)). For example, retinoids have been shown to be vital to the maintenance of skin homeostasis and barrier function in mammals (Fisher, G. J., and Voorhees, J. J.,
FASEB J.
10:1002-1013 (1996)). Retinoids are also apparently crucial during embryogenesis, since offspring of dams with vitamin A deficiency (VAD) exhibit a number of developmental defects (Wilson, J. G., et al.,
Am. J. Anat.
92:189-217 (1953); Morriss-Kay, G. M., and Sokolova, N.,
FASEB J.
10:961-968 (1996)). With the exceptions of those on vision (Wald, G., et al.,
Science
162:230-239 (1968)) and spernatogenesis in mammals (van Pelt, H. M. M., and De Rooij, D. G.,
Endocrinology
128:697-704 (1991)), most of the effects generated by VAD in animals and their fetuses can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al.,
Am. J. Anat.
92:189-217 (1953); Thompson etal.,
Proc. Royal Soc.
159:510-535 (1964); Morriss-Kay, G. M., and Sokolova, N.,
FASEB J.
10:961-968 (1996)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E.,
Teratology
5, 103-108 (1972); Kessel, M.,
Development
115:487-501 (1992); Creech Kraft, J., In
Retinoids in Normal Development and Teratogenesis
, G. M. Morriss-Kay, ed., Oxford University Press, Oxford, UK, pp. 267-280 (1992)), and the marked effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi et al.,
Nature
355:352-353 (1992); Tabin, C. J.,
Cell
66:199-217 (1991)), have contributed to the notion that RA may have critical roles in morphogenesis and organogenesis.
Retinoid Receptors
Except for those involved in visual perception (Wald, G. et al.,
Science
162:230-239 (1968)), the molecular mechanisms underlying the highly diverse effects of retinoids have until recently remained obscure. The discovery of nuclear receptors for RA (Petkovich et al.,
Nature
330:444-450 (1987); Giguère et al.,
Nature
330:624-629 (1987)) has greatly advanced the understanding of how the retinoids may exert their pleiotropic effects (Leid et al.,
TIBS
17:427-433 (1992); Linney, E.,
Current Topics in Dev. Biol.
27:309-350 (1992)). Since this discovery it has become apparent that the genetic activities of the RA signal are mediated through two families of receptors—the RAR family and the RXR family—which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamnin D3 receptors (for reviews see Leid et al.,
TIBS
17:427-433 (1992); Chambon, P.,
Semin. Cell Biol.
5:115-125 (1994); Chambon, P.,
FASEB J.
10:940-954 (1996); Giguere, V.,
Endocrinol. Rev.
15:61-79 (1994); Mangelsdorf, D. J., and Evans, R. M.,
Cell
83:841-850 (1995); Gronemeyer, H., and Laudet, V.,
Protein Profile
2:1173-1236 (1995)).
RAR Receptors
Receptors belonging to the RAR family (RAR&agr;, &bgr; and &ggr; and their isoforms) are activated by both all-trans- and 9-cis-RA (Leid et al.,
TIBS
17:427-433 (1992); Chambon, P.,
Semin. Cell Biol.
5:115-125 (1994); Dollé, P., et al.,
Mech. Dev.
45:91-104 (1994); Chambon, P.,
FASEB J.
10:940-954 (1996)). Within a given species, the DNA binding (C) and the ligand binding (E) domains of the three RAR types are highly similar, whereas the C-terminal domain F and the middle domain D exhibit no or little similarity. The amino acid sequences of the three RAR types are also notably different in their B regions, and their main isoforms (&agr;1 and &agr;2, &bgr;1 to &bgr;1&bgr;4, and &ggr;1 and &ggr;2) further differ in their N-terminal A regions (Leid et al.,
TIBS
17:427-433 (1992)). Amino acid sequence comparisons have revealed that the interspecies conservation of a given RAR type is greater than the similarity found between the three RAR types within a given species (Leid et al.,
TIBS
17:427-433 (1992)). This interspecies conservation is particularly striking in the N-terminal A regions of the various RAR&agr;, &bgr; and &ggr; isoforms, whose A region amino acid sequences are quite divergent. Taken together with the distinct spatio-temporal expression patterns observed for the transcripts of each RAR and RXR type in the developing embryo and in various adult mouse tissues (Zelent, A., et al.,
Nature
339:714-717 (1989); Dollé, P., et al.,
Nature
342:702-705 (1989); Dollé et al.,
Development
110:1133-1151 (1990); Ruberte et al.,
Development
108:213-222 (1990); Ruberte et al.,
Development
111:45-60 (1991), Mangelsdorf et al.,
Genes
&
Dev.
6:329-344 (1992)), this interspecies conservation has suggested that each RAR type (and isoform) may perform unique functions. This hypothesis is further supported by the finding that the various RAR isoforms contain two transcriptional activation functions (AFs) located in the N-terminal A/B region (AF-1) and in the C-terminal E region (AF-2), which can synergistically, and to some extent differentially, activate various RA-responsive promoters (Leid et al.,
TIBS
17:427-433 (1992); Nagpal, S., et al.,
Cell
70:1007-1019 (1992); Nagpal, S., et al.,
EMBO J.
12:2349-2360 (1993)).
RXR Receptors
Unlike the RARs, members of the retinoid X receptor family (RXR&agr;, &bgr; and &ggr;) are activated exclusively by 9cis-RA (Chambon, P.,
FASEB J.
10:940-954 (1996); Chambon, P.,
Semin. Cell Biol.
5:115-125 (1994); Dollé, P., et al.,
Mech. Dev.
45:91-104 (1994); Linney, E.,
Current Topics in Dev. Biol.
27:309-350 (1992); Leid et al.,
TIBS
17:427-433 (1992); Kastner et al., in
Vitamin A in Health and Disease
, R. Blomhoff, ed., Marcel Dekker, New York (1993)). However, the RXRs characterized to date are similar to the RARs in that the different RXR types also differ markedly in their N-terminal A/B regions (Leid et al.,
TIBS
17:427433 (1992); Leid et al.,
Cell
68:377-395 (1992); Mangelsdorf et al.,
Genes and Dev.
6:329-344 (1992)), and contain the same transcriptional activation functions in their N-terminal A/B region and C-terminal E region (Leid et al.,
TIBS
17:427-433 (1992); Nagpal, S., et al.,
Cell
70:1007-1019 (1992); Nagpal, S., et al.,
EMBO J.
12:2349-2360 (1993)).
RXR&agr; and RXR&bgr; have a widespread (possibly ubiquitous) expression pattern during mouse development and in the adult animal, being found in all fetal and adult tissues thus far examined (Mangelsdorf, D. J., et al.,
Genes
&
Devel.
6:329-344 (1992); Dollé, P., et al.,
Mech. Devel.
45:91-104 (1994); Nagata, T., et al.,
Gene
142:183-189 (1994)). RXR&ggr; transcripts, however, appear to have a more restricted distribution, being expressed in developing skeletal muscle in the embryo (where their expression persists throughout life), in the heart (after birth), in sensory epithelia of the visual and auditory systems, in specific structures of the central nervous system, and in tissues involved in thyroid hormone homeostasis, e.g, the thyroid gland and thyrotrope cells in the pituitary (Mangelsdorf, D. J., et al.,
Genes
&
Devel.
6:329-344 (1992); Dollé, P., et al.,
Mech. Devel.
45:91-104 (1994); Sugawara, A., et al.,
Endocrinology
136:1766-1774 (1995); Liu, Q., and Linney, E.,
Mol. Endocrinol.
7:651-658 (1993)).
It is currently unclear whether all the molecular pro
Chambon Pierre
Gronemeyer Hinrich
Ostrowski Jacek
Reczek Peter R.
Bristol--Myers Squibb Company
Jones Dwayne C.
Sterne Kessler Goldstein & Fox P.L.L.C.
LandOfFree
Therapeutic combinations of RAR antagonists and RXR agonists... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutic combinations of RAR antagonists and RXR agonists..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic combinations of RAR antagonists and RXR agonists... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3147100