Retinoic acid receptor antagonists as promoters of angiogenesis

Details Retinoic acid receptor antagonists as promoters of angiogenesis Retinoic acid receptor antagonists as promoters of angiogenesis

2001-09-13

2004-03-30

Nazario-Gonzalez, Porfirio (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C562S490000, C562S492000

Reexamination Certificate

active

06713515

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compositions comprising a retinoic acid receptor antagonist capable of promoting angiogenesis. The invention also relates to methods of treating medical conditions associated with suboptimal angiogenesis.
BACKGROUND OF THE INVENTION
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 Sporn et al.,
The Retinoids
, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)).
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 retinoic acid (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, M., et al.,
TIBS
17:427-433 (1992); Linney, E.,
Current Topics in Dev. Biol
. 27:309-350 (1992)). It is thought that the effects of the RA signal are mediated through two families of receptors—the RAR family and RXR family—which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamin D3 receptors (for reviews, see Leid, M., 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)).
Receptors belonging to the retinoic acid receptor family (RAR&agr;, &bgr; and &ggr; and their isoforms) are activated by both all-trans- and 9-cis-RA (Leid, M., 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)). Unlike the RARs, members of the retinoid X receptor family (RXR&agr;, &bgr; and &ggr;) are activated exclusively by 9-cis- RA (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, M., 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)).
It has been shown that activation of RA-responsive promoters likely occurs through RAR/RXR heterodimers rather than through homodimers (Yu, V. C., et al.,
Cell
67:1251-1266 (1991); Leid, M., et al.,
Cell
68:377-395 (1992b); Durand et al.,
Cell
71:73-85 (1992); Nagpal, S., et al.,
Cell
70:1007-1019 (1992); Zhang, X. K., et al.,
Nature
355, 441-446 (1992); Kliewer et al.,
Nature
355:446-449 (1992); Bugge et al.,
EMBO J
. 11:1409-1418 (1992); Marks et al.,
EMBO J
. 11:1419-1435 (1992); Yu, V. C. et al.,
Cur. Op. Biotech
. 3:597-602 (1992); Leid, M., et al.,
TIBS
17:427-433 (1992); Laudet and Stehelin,
Curr. Biol
. 2:293-295 (1992); Green, S.,
Nature
361:590-591 (1993)). The RXR portion of these heterodimers has been proposed to be silent in retinoid-induced signaling (Kurokawa, R., et al.,
Nature
371:528-531 (1994); Forman, B. M., et al.,
Cell
81:541-550 (1995); Mangelsdorf, D. J., and Evans, R. M.,
Cell
83:835-850 (1995); Vivat, V. et al.,
EMBO J
. 16:5697-5709 (1997)) but conflicting results have been reported as far as the ligand-binding ability of RXR in heterodimers is concerned (Kurokawa, R., et al.,
Nature
371:528-531 (1994); Chen, J.-Y. et al.,
Nature
382:819-822 (1996); Kersten, S. et al.,
Biochem
. 35:3816-3824 (1996); Chen, Z. et al.,
J. Mol. Biol
. 275:55-65 (1998); Li, C. et al.,
Proc. Natl. Acad. Sci. USA
94:2278-2283 (1997). The results of these and of genetic studies strongly suggest that RAR/RXR heterodimers are indeed functional units that transduce the RA signal in vivo (Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Kastner, P. et al.,
Cell
83:859-869 (1995); Mascrez, B. et al.,
Development
125:4691-4707 (1998)). Thus, the basis for the highly pleiotropic effect of retinoids may reside, at least in part, in the control of different subsets of retinoid-responsive promoters by cell-specifically expressed heterodimeric combinations of RAR/RXR subtypes (and isoforms), whose activity may be in turn regulated by cell-specific levels of all-trans- and 9-cis-RA (Leid, M., et al.,
TIBS
17:427-433 (1992)).
Angiogenesis is a complex multistep process involving the formation of new blood vessels from preexisting vessels. The mammalian vasculature consists of large arteries that branch into smaller vessels turning into precapillary arterioles that terminate into a capillary network. The vessel wall is composed of endothelial, smooth muscle and fibroblast cells. Capillaries, on the other hand, are comprised almost entirely of endothelial cells. The endothelium plays a prominent role in the vascular function, being constantly exposed to cytokines, vasoactive factors, procoagulants and mechanical signals (Ross, 1993). Angiogenesis is dependent on endothelial cell migration, proliferation, proteolytic activity and morphogenesis (Hanahan, 1996).
A number of growth factors, such as VEGF and bFGF, are known to positively affect angiogenesis. Such therapeutic manipulation of vessel growth is an attractive approach to promote revascularization. However, the availability of a small molecular modulator of this process would provide a break-through for the treatment of diseases and conditions related to insufficient angiogenesis.
SUMMARY OF THE INVENTION
The present invention provides a novel method for promoting angiogenesis. The method comprises treating a mammal in need of such therapy with a retinoic acid receptor (RAR) antagonist. The RAR antagonist therapy of the present invention can be used to treat any medical condition associated with suboptimal angiogenesis, such as ischemia and scleroderma. The application of RAR antagonist therapy also finds broad application in the treatment of dermatology, pulmonary and cardiovascular diseases. Applications also include, but are not limited to, promoting angiogenesis for optimal organ function, recanalization of thrombi, development of collateral blood supply for ischemic tissues, including cardiac ischemia, as well as salvage of infarcted myocardium. The use of RAR antagonist therapy to stimulate angiogenesis is also beneficial for the treatment of respiratory aliments such as asthma, emphysema and chronic obstructive pulmonary disease (COPD) where loss of capillary area may promote hypertension and tissue ischemia. The use of RAR antagonist therapy is also beneficial for the treatment of bone fracture.


REFERENCES:
patent: 5317090 (1994-05-01), Blaudin De The et al.
patent: 5559248 (1996-09-01), Starrett, Jr. et al.
patent: 5618839 (1997-04-01), Starrett, Jr. et al.
patent: 5728846 (1998-03-01), Vuligonda et al.
patent: 5849923 (1998-12-01), Starrett, Jr. et al.
patent: 5877207 (1999-03-01), Klein et al.
patent: 5919970 (1999-07-01), Song et al.
patent: 5973007 (1999-10-01), Demarchez et al.
patent: 5998395 (1999-12-01), Kligman
patent: 5998654 (1999-12-01), Boehm et al.
patent: 6001885 (1999-12-01), Vega et al.
patent: 6025388 (2000-02-01), Nagpal et al.
patent: 6028088 (2000-02-01), Pershadsingh et al.
patent: 6034110 (2000-03-01), Nagpal et al.
patent: 6063797 (2000-05-01), Fesus et al.
patent: 6083973 (2000-07-01), Belloni
patent: 6087505 (2000-07-01), Vuligonda et al.
patent: 6093838 (2000-07-01), Vasudevan et al.
patent: 6127382 (2000-10-01), Beard et al.
patent: 6166244 (2000-12-01), Beard et al.
patent: 6177588 (2001-01-01), Beard et al.
patent: 6225494 (2001-05-01), Song et al.
patent: 6319948 (2001-11-01), Tramposch et al.
patent: 6326397 (2001-12-01), Bollag et al.
patent: 661259 (1997-10-01), None
patent: WO 97/09297 (1997-03-01), None
patent: WO 98/08546 (1998-03-01), None
patent: WO 98/36746 (1998-08-01), None
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