Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2000-06-09
2002-09-17
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S419000, C556S428000, C556S438000, C556S440000, C556S422000, C546S014000, C548S110000, C548S406000, C549S214000
Reexamination Certificate
active
06452032
ABSTRACT:
FIELD OF THE INVENTION
The present invention is relevant to the fields of human and veterinary medicine, physiology and biochemistry, particularly in the regulation of cellular proliferation and lipid metabolism in a mammal.
BACKGROUND OF THE INVENTION
A vast array of specific metabolic, developmental, and catabolic processes appear to be directly or indirectly regulated in vivo by comparatively small molecules such as steroids, retinoids and thyroid hormones. The mechanism whereby a single such compound can contribute to the regulation of numerous different cellular events was the subject of much speculation until relatively recently, when it was discovered that these compounds each share the ability to bind to transcriptionally active proteinaceous receptors. These protein receptors, in turn, are able to bind specific cis-acting nucleic acid regulatory sequence regions, termed response elements or RE's, located upstream of the coding sequence of certain genes and to activate the transcription of these genes. Thus, the proteinaceous receptors can serve as specific, ligand-dependent regulators of gene transcription and expression.
The amino acid sequences of these various receptors were quickly found to share regions of homology, thus making each such receptor a member of a family of ligand-modulated receptor molecules. This family has been termed the steroid superfamily of nuclear hormone receptors; nuclear, because the receptors are usually found in high concentration in the nucleus of the cell.
Further study of the structural and functional relationship between the nuclear hormone receptors has shown certain characteristics in common between them in addition to sequence homology. See e.g., Evans et al.
Science
240:889-895 (1988). As stated above, the nuclear hormone receptors are able to bind to cis-acting regulatory elements present in the promoters of the target genes. The glucocorticoid, estrogen, androgen, progestin, and mineralcorticoid receptors have been found to bind as homodimers to specific response elements organized as inverted repeats.
Another class of nuclear hormone receptors, which includes the retinoid receptor RAR (retinoic acid receptor), the thyroid receptor, the vitamin D receptor, the peroxysome proliferator receptor, and the insect ecdysone receptor bind the response element as a heterodimer in conjunction with the retinoid X receptor (RXR), which is positively activated by 9-cis retinoic acid. See Mangelsdorf, et al.,
The Retinoid Receptors in The Retinoids: Biology, Chemistry and Medicine
Ch.8 (Sporn et al., eds. 2d ed., Raven Press Ltd. 1994); Nagpal and Chandraratna,
Current Pharm. Design
2:295-316 (1996), which are both incorporated by reference herein. The retinoid receptors RAR and RXR, like many nuclear hormone receptors, exist in a number of subtypes (RAR&agr;, RAR&bgr;, RAR&ggr;, and RXR&agr;, RXR&bgr;, and RXR&ggr;). Additionally, each subtype may exist in different isoforms.
Another such receptor is a relatively recently characterized nuclear hormone receptor termed farnesoid X-activated receptor (FXR). Foreman et al.,
Cell
81:687-693 (1995) have demonstrated that this receptor termed farnesoid X-activated receptor (FXR), is activated by farnesol and related molecules. This reference is hereby incorporated by reference herein. FXR expression is largely restricted to the liver, gut, adrenal gland, and kidney.
Common to other nuclear hormone receptors, the amino acid sequence of FXR reveals a conserved DNA-binding domain (DBD) and ligand-binding domain (LBD). The LBD comprises subdomains responsible for ligand binding, receptor dimerization, and transactivation. Additionally, cells expressing chimeric proteins that contain the LBD of FXR fused to the DBD of the yeast GAL4 transcription activator did not transcribe a reporter gene containing a GAL4 response element unless the FXR construct was coexpressed with another protein comprising the dimerization and ligand binding subdomains of RXR. These data suggested that FXR and RXR interact to form a transcriptionally active dimer. No interaction was seen between FXR and any other nuclear hormone receptor. Id.
FXR has been recently discovered to be an important regulator of bile acid synthesis. When bound by an appropriate ligand FXR is activated, and functions to regulate the expression of Cyp7a, thereby controlling a key stage in the degradation of cholesterol, the precursor of the bile acids and the steriod hormones. See Wang, et al.,
Molec. Cell
3:543-553 (May 1999), hereby incorporated by reference herein.
SUMMARY OF THE INVENTION
The present invention is directed to silicone-containing organic compounds is and compositions comprising such compounds having the general structure indicated in Formulae 1-4, infra. Such compounds are useful to modulate the transcription-regulating activity of a nuclear hormone receptor, such as, without limitation, a retinoic acid receptor (RAR), a retinoid X receptor (RXR), a farnesoid receptor (FXR), perioxisome proliferator activated receptor (PPAR) and the like. Certain such compounds are ligands of either or both an RAR or an RXR, and able to cause the retinoid receptor to suppress, inhibit, or stimulate the transcription of a given target gene. Preferably, in this embodiment of the present invention the claimed compounds are substantially specific in their activity towards either RXR or RAR, and do not activate or inhibit any other nuclear hormone receptor.
Certain compounds of the present invention may have activity at one or more nuclear hormone receptor other than a retinoid receptor, such as, without limitation, FXR, PPAR, TR, DAX, CAR. Preferably, the compound is active as a modulator of FXR activity. It is also preferred, although not essential, that the compound is not substantially active as a modulating ligand of other nuclear hormone receptors.
It has also been discovered that the compounds of the present invention have activity as agonists, antagonists, or inverse agonists of the transactivation activity of nuclear hormone receptors. Certain compounds of the present invention have RAR and/or RXR agonist activity in a transactivation assay using a reporter gene as a transcription template.
Certain compositions of the invention comprise a compound active as an FXR agonist or antagonist that is able to modulate concentrations of plasma cholesterol in a mammal. In another embodiment the FXR agonist may be used to increase the concentration of cholesterol within a hypocholesteremic mammal. As stated above, FXR has been discovered to inhibit Cyp7a expression when bound and activated by bile acids. Thus, an antagonist of FXR would prevent the bile acid-initiated inhibition of Cyp7a synthesis.
The nuclear hormone receptor ligands of the present invention may be receptor agonists, receptor antagonists, or receptor inverse agonists. By “agonist” is meant that the ligand stimulates a ligand-dependent receptor-characteristic activity above any baseline levels present in the absence of ligand. By “receptor-characteristic activity” is meant the direct or indirect inhibition or stimulation of gene expression, which expression is regulated by the receptor in question. By “antagonist” is meant that the ligand binds to the receptor and functions as a competitive or non-competitive inhibitor of receptor-characteristic agonist activity. By “inverse agonist” or “reverse agonist” is meant that the ligand will bind to the receptor in question and cause the suppression of receptor activity lower than the amount of activity seen in the absence of receptor ligand.
Thus, the present invention pertains to compositions comprising, consisting essentially of, or consisting of a compound selected from the group consisting of Formulas 1, 2, 3 and 4
wherein the dashed line represents a bond or absence of a bond;
X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
X is (C(R
1
)
2
)
n
where R
1
is H or alkyl of 1 to 6 carbons, and n is an integer having the value of 0 or 1;
R
2
is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF
3
,
Beard Richard L.
Chandraratna Roshantha A.
Garst Michael E.
Allergan Sales, LLC
Baran Robert J.
Fisher Carlos A.
Shaver Paul F.
Voet Martin A.
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