Means for the modulation of processes mediated by retinold...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C514S001000

Reexamination Certificate

active

06576676

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to intracellular receptors, and ligands therefor. In a particular aspect, the present invention, relates to methods for modulating processes mediated by retinoid receptors.
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 in response to exogenous inducers such as hormones or growth factors. As part of the scientific attack on this problem, a great deal of work has been done in efforts to identify exogenous inducers which are capable of mediating specific gene regulation.
Although much remains to be learned about the specifics of gene regulation, it is known that exogenous inducers modulate gene transcription by acting in concert with intracellular components, including intracellular receptors and discrete DNA sequences known as hormone response elements (HREs).
As additional members of the steroid/thyroid superfamily of receptors are identified, the search for exogenous inducers for such newly discovered receptors (i.e., naturally occurring (or synthetic) inducers) has become an important part of the effort to learn about the specifics of gene regulation.
The retinoid members of the steroid/thyroid superfamily of receptors, for example, are responsive to compounds referred to as retinoids, which include retinoic acid, retinol (vitamin A), and a series of natural and synthetic derivatives which have been found to exert profound effects on development and differentiation in a wide variety of systems.
The identification of compounds which interact with retinoid receptors, and thereby affect transcription of genes which are responsive to retinoic acid (or other metabolites of vitamin A), would be of significant value, e.g., for therapeutic applications.
Recently, a retinoic acid dependent transcription factor, referred to as RAR-alpha (retinoic acid receptor-alpha), has been identified. Subsequently, two additional RAR-related genes have been isolated; thus there are now at least three different RAR subtypes (alpha, beta and gamma) known to exist in mice and humans. These retinoic acid receptors (RARs) share homology with the superfamily of steroid hormone and thyroid hormone receptors and have been shown to regulate specific gene expression by a similar ligand-dependent mechanism [Umesono et al., Nature 336: 262 (1988)]. These RAR subtypes are expressed in distinct patterns throughout development and in the mature organism.
More recently, additional novel members of the steroid/thyroid superfamily of receptors have been identified, such as, for example, retinoid X receptor-alpha [RXR-&agr;; see Mangelsdorf et al., in Nature 345: 224-229 (1990)], retinoid X receptor-beta [RXR-&bgr;; see Hamada et al., Proc. Natl. Acad. Sci. USA 86: 8289-8293 (1989)], and retinoid X receptor-gamma [RXR-&ggr;; see Mangelsdorf et al., Genes and Development 6:329-344 (1992)]. While these novel receptors are responsive to retinoic acid, the primary exogenous inducer(s) for these receptors have not been identified.
Although both RAR and RXR respond to retinoic acid in vivo, the receptors differ in several important aspects. First, RAR and RXR are significantly divergent in primary structure (e.g., the ligand binding domains of RAR&agr; and RXR&agr; have only 27% amino acid identity). These structural differences are reflected in different relative degrees of responsiveness of RAR and RXR to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RAR and RXR. In contrast to the RARs, which are not expressed at high levels in the visceral tissues, RXR&agr; mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine. Finally, response elements have recently been identified in the cellular retinol binding protein type II (CRBPII) and apolipoprotein AI genes which confer responsiveness to RXR, but not RAR. Indeed, RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element. These data, in conjunction with the observation that both RAR and RXR can activate through the RAR response element of the RAR&bgr; promoter, indicate that the two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
In view of the related, but clearly distinct nature of these receptors, the identification of ligands which are more selective for the retinoid X receptor than is retinoic acid would be of great value in selectively controlling processes mediated by one or both of these retinoid receptor types.
Other information helpful in the understanding and practice of the present invention can be found in commonly assigned, co-pending U.S. patent application Ser. Nos. 108,471, filed Oct. 20, 1987 (now issued as U.S. Pat. No. 5,071,773); 276,536, filed Nov. 30, 1988 (now issued as U.S. Pat. No.4,981,784); 325,240, filed Mar. 17, 1989; 370,407, filed Jun. 22, 1989; and 438,757, filed Nov. 16, 1989, all of which are hereby incorporated herein by reference in their entirety.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have developed methods to modulate retinoid receptor mediated processes, employing high affinity, high specificity ligands for such receptors.
In a particular aspect of the present invention, there are provided ligands which are high affinity, high specificity ligands for retinoid receptors. Thus, in one aspect of the present invention, there are provided ligands which are more selective for the retinoid X receptor than is all-trans-retinoic acid. In another aspect of the present invention, we have discovered alternative ligands (other than all-trans-retinoic acid) which are capable of inducing retinoic acid receptor mediated processes.
In yet another aspect of the present invention, we have developed methods for the preparation of such retinoid receptor ligands from readily available retinoid compounds.


REFERENCES:
patent: 4877805 (1989-10-01), Kligman
patent: 4981784 (1991-01-01), Evans et al.
patent: 5071773 (1991-12-01), Evans et al.
patent: 5183817 (1993-02-01), Bazzano
patent: 5192534 (1993-03-01), Grollier et al.
patent: 5219888 (1993-06-01), Katocs, Jr. et al.
patent: 5428071 (1995-06-01), Bollag et al.
patent: 5932622 (1999-08-01), Evans et al.
patent: 5968989 (1999-10-01), Evans et al.
patent: A-0376821 (1990-07-01), None
patent: 0552624 (1993-07-01), None
patent: A-2619309 (1989-02-01), None
patent: A-4253934 (1992-09-01), None
patent: WO 9311755 (1993-06-01), None
Wada et al., “Synthesis of 9Z-9-Substituted Retinoic Acids by Palladium Catalyzed Coupling Reaction of a Vinyl Triflate with Alkenyl Stannates” (2000) Chem. Pharm. Bull., 48(9), 1391-1394.*
Akita et al., “Nonbleachable Rhodopsins Retaining the Full Natural Chromophore”,J. Am. Chem. Soc.102:6370-6372 (1980).
Allegretto et al., “Immunochemical Detection of Unique Proteolytic Fragments of the Chick 1,25-Dihydroxyvitamin D3Receptor”J. of Biol. Chem.262(3):1312-1319 (1987).
Allenby et al., “Retinoic acid receptors and retinoid X receptors: Interactions with endogenous retinoic acids”Proc. Natl. Acad. Sci. USA90:30-34 (1993).
Asato et al., “Retinal and Rhodopsin Analogues Directed toward a Better Understanding of the H.T.-n Model of the Primary Process of Vision”J. Am. Chem. Soc.108:5032-5033 (1986).
Bridges and Alvarez, “Measurement of the Vitamin A Cycle”Methods in Enzymology81:463-485 (1982).
Corey et al., “New Methods for the Oxidation of Aldehydes to Carboxlic Acids and Esters”J. Am. Chem. Soc.90(20):5616-5617 (1968).
Derguini and Nakanishi, “Synthetic rhodopsin analogs”Photobiochemistry and Photobiophysics13:259-279 (1986).
Durand et al., “All-Trans and 9-Cis Retinoic Acid Induction of CRABPII Transcription Is Mediated by RAR-RXR Heterodimers Bound to DR1 and DR2 Repeated Motifs”Cell71:73-85 (1992).
Eager et al., “A member of the chicken RXR family of nuclear receptors activates transcription in respon

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Means for the modulation of processes mediated by retinold... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Means for the modulation of processes mediated by retinold..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Means for the modulation of processes mediated by retinold... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3151014

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.