Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-09-14
2003-07-15
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S444000, C562S426000, C514S561000, C514S562000, C514S571000, C546S339000
Reexamination Certificate
active
06593493
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to small molecule compounds that are able to modulate the biological activity of retinoid X receptors, and to methods for the production and therapeutic use of such compounds.
BACKGROUND OF THE INVENTION
The vitamin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. For example, retinoic acid-containing products, such as Retin-A® and Accutane®, have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Many of these synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid, and thus have therapeutic potential for the treatment of numerous disease states.
Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis as well as cancers such as Kaposi's Sarcoma. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds have clear effects on cellular proliferation, differentiation and programmed cell death (apoptosis), and thus, may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as acute promyleocytic leukemia (APL), epithelial cancers, squamous cell carcinomas, including cervical and skin cancers and renal cell carcinoma. Furthermore, retinoids may have beneficial activity in treating and preventing diseases of the eye, cardiovascular disease and skin disorders.
Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member of the steroid/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. V. Giguere et al.,
Nature
, 330:624-29 (1987); M. Petkovich et al.,
Nature
, 330: 444-50 (1987); for a review, see R. M. Evans,
Science
, 240:889-95 (1988). It is now known that retinoids regulate the activity of two distinct intracellular receptor subfamilies: the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs), including their subtypes, RAR&agr;,&bgr;,&ggr; and RXR&agr;,&bgr;,&ggr;. All-trans-retinoic acid (ATRA) is an endogenous low-molecular-weight ligand that modulates the transcriptional activity of the RARs, while 9-cis retinoic acid (9-cis) is the endogenous ligand for the RXRs. R. A. Heyman et al.,
Cell
, 68:397-406 (1992); and A. A. Levin et al.,
Nature
, 355:359-61 (1992).
Although both the RARs and RXRs respond to ATRA in vivo, due to the in vivo conversion of some of the ATRA to 9-cis, the receptors differ in several important aspects. First, the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RAR&agr; and RXR&agr; have only approximately 30% amino acid homology). These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs. For example, RXR&agr; mRNA is expressed at high levels in the visceral tissues, e.g., liver, kidney, lung, muscle and intestine, while RAR&agr; mRNA is not. Finally, the RARs and RXRs have different target gene specificity. In this regard, RARs and RXRs regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of the consensus sequence AGGTCA. RAR:RXR heterodimers activate transcription ligand by binding to direct repeats spaced by five base pairs (a DR5) or by two base pairs (a DR2). However, RXR:RXR homodimers bind to a direct repeat with a spacing of one nucleotide (a DR1). D. J. Mangelsdorf et al., “The Retinoid Receptors” in
The Retinoids: Biology, Chemistry and Medicine
, M. B. Sporn, A. B. Roberts and D. S. Goodman, Eds., Raven Press, New York, N.Y., 2nd Edition (1994). For example, response elements have been identified in the cellular retinal binding protein type II (CRBPII), which consists of a DR1, and in Apolipoprotein AI genes that confer responsiveness to RXR, but not to RAR. Further, RAR has also been shown to repress RXR-mediated activation through the CRBPII RXR response element (D. J. Manglesdorf et al.,
Cell
, 66:555-61 (1991)). Also, RAR specific target genes have been identified, including target genes specific for RAR&bgr; (e.g., &bgr;RE), that consist of a DR5. These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
RXR agonists in the context of an RXR:RXR homodimer display unique transcriptional activity in contrast to the activity of the same compounds through an RXR heterodimer. Activation of a RXR homodimer is a ligand dependent event, i.e., the RXR agonist must be present to bring about the activation of the RXR homodimer. In contrast, RXR working through a heterodimer (e.g., RXR:RAR, RXR:VDR) is often the silent partner, i.e., no RXR agonist will activate the RXR-containing heterodimer without the corresponding ligand for the heterodimeric partner. However, for other heterodimers, (e.g., PPAR:RXR) a ligand for either or both of the heterodimer partners can activate the heterodimeric complex. Furthermore, in some instances, the presence of both an RXR agonist and the agonist for the other heterodimeric partner (e.g., gemfibrizol for PPAR&agr; and TTNPB for RAR&agr;) leads to at least an additive, and often a synergistic enhancement of the activation pathway of the other IR of the heterodimer pair (e.g., the PPAR&agr; pathway). See e.g., WO 94/15902, published Jul. 21, 1994; R. Mukherjee et al.,
J. Steroid Biochem. Molec. Biol
., 51:157-166 (1994); and L. Jow and R. Mukherjee,
J. Biol. Chem
., 270:3836-40 (1995).
RAR and RXR retinoid agonists, including both RAR specific and RXR specific agonists have been previously identified. See e.g., WO 94/15902, WO 93/21146, WO 94/15901, WO 94/12880, WO 94/17796, WO 94/20093, WO 96/05165 and Application No. PCT/US93/10166; EPO Patent Application Nos. 87110303.2, 87309681.2 and EP 0718285; U.S. Pat. Nos. 4,193,931, 4,539,134, 4,801,733, 4,831,052, 4,833,240, 4,874,747, 4,879,284, 4,898,864, 4,925,979, 5,004,730, 5,124, 473, 5,198,567, 5,391,569 and Re 33,533; and H. Kagechika et al., “Retinobenzoic Acids. 2. Structure-Activity Relationship of Chalcone-4-carboxylic Acids and Flavone-4′-carboxylic Acids”,
J. Med. Chem
., 32:834 (1989); H. Kagechika et al., “Retinobenzoic Acids. 3. Structure-Activity Relationships of Retinoidal Azobenzene-4-carboxylic Acids and Stilbene-4-carboxylic Acids”,
J. Med. Chem
., 32:1098 (1989); H. Kagechika et al., “Retinobenzoic Acids. 4. Conformation of Aromatic Amides with Retinoidal Activity. Importance of trans-Amide Structure for the Activity”,
J. Med. Chem
., 32:2292 (1989); M. Boehm et al.,
J. Med. Chem
., 37:2930 (1994); M. Boehm et al.,
J. Med. Chem
., 38:3146 (1995); E. Allegretto et al.,
Journal of Biol. Chem
., 270:23906 (1995); R. Bissonnette et al.,
Mol
. &
Cellular Bio
., 15:5576 (1995); R. Beard et al.,
J. Med. Chem
., 38:2820 (1995); and M. I. Dawson et al., “Effect of Structural Modifications in the C7-C11 Region of the Retinoid Skeleton on Biological Activity in a Series of Aromatic Retinoids”,
J. Med. Chem
., 32:1504 (1989).
Further, antagonists to the RAR subfamily of receptors have been identified. See e.g., C. Apfel et al.,
Proc. Natl. Acad. Sci
., 89:7129 (1992); S. Keidel et al.,
Mol. Cell. Biol
., 14:287 (1994); S. Kaneko et al.,
Med. Chem. Res
., 1:220 (1991); L. Eyrolles et al.,
Med. Chem. Res
., 2:361 (1992); J. Eyrolles et al.,
J. Med. Chem
., 37:1508 (1994); M-O Lee et al.,
Proc. Natl. Acad. Sci
., 91:5632 (1994); Yoshimura et al.,
J. Med. Chem
., 38:3163
Ardecky Robert J.
Boehm Marcus F.
Chen Jyun-Hung
Faulkner Amy L.
Hamann Lawrence G.
Killos Paul J.
Ligand Pharmaceuticals Inc.
Paul Hastings Janofsky & Walker LLP
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