Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-07
2003-01-14
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S364000, C514S374000, C548S131000, C548S136000, C548S143000, C548S235000, C548S236000
Reexamination Certificate
active
06506781
ABSTRACT:
The present invention relates to compounds that bind to and affect PPAR-alpha, PPAR-gamma, and PPAR-delta. In another aspect, the present invention relates to methods for prevention or treatment of PPAR-gamma mediated diseases and conditions, and to methods for design of antagonists of PPAR-alpha, PPAR-gamma, and PPAR-delta. In another aspect, the present invention relates to compounds that bind to and affect FXR, LXR-alpha, and LXR-beta. In another aspect, the present invention relates to methods for the prevention or treatment of diseases mediated by FXR, LXR-alpha, and LXR-beta, and to methods for the design of antagonists of FXR, LXR-alpha, and LXR-beta.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Willson, T. M. and Wahli, W.,
Curr. Opin. Chem. Biol
., (1997), Vol. 1, pp 235-241.
Three mammalian PPARs have been identified which are termed PPAR-alpha, PPAR-gamma, and PPAR-delta. PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor. These DNA response elements (PPRE) have been identified in the regulatory regions of a number of genes encoding proteins involved in lipid metabolism and energy balance. The biological role of the PPARs in the regulation of lipid metabolism and storage has been recently reviewed. See, for example, Spiegelman, B. M.,
Diabetes
, (1998), Vol. 47, pp 507-514, Schoonjans, K., Martin, G., Staels, B., and Auwerx, J.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 159-166, and Brun, R. P., Kim, J. B., Hu, E., and Spiegelman, B. M.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 212-218.
PPAR-gamma ligands of the thiazolidinedione class (TZD) enhance the actions of insulin in man and reduce circulating glucose levels in rodent models of diabetes. The PPAR-gamma receptor is expressed in adipose tissue and plays a pivotal role the regulation of adipocyte differentiation in vitro. TZD such as rosiglitazone induce adipocyte differentiation in vitro through activation of the PPAR-gamma receptor. Although there are clearly therapeutic uses for PPAR-gamma ligands in the treatment of diseases of lipid metabolism and energy balance, it is possible that there will be side effects of these drugs. For example, PPAR-gamma ligands that promote adipocyte differentiation in vivo could lead to increased fat accumulation and weight gain. This side effect might offset the beneficial effects of a PPAR-gamma ligand in the treatment of diabetes or other diseases where obesity is a risk factor. See, for example, the Spiegelman and Brun articles cited above.
Essential dietary fatty acids and certain of their eicosanoid metabolites are naturally occurring hormones for the PPAR receptors (Kliewer, 1997; Kliewer 1995). These hormones can promote adipogenesis through activation of the PPAR-gamma receptor. See, for example, Kliewer, S. A., et al.,
Proc. Natl. Acad. Sci. USA
, (1997), Vol. 94, pp 4318-4323, and Kliewer, S. A., et al., Cell, (1995), Vol. 83, pp 813-819. Molecules that inhibit the adipogenic effects of endogenous PPAR-gamma hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage. See, for example, Tontonoz, P., Hu, E., and Spiegelman, B. M.,
Curr. Opin. Genet. Dev
., (1995), Vol. 5, pp 571-576. Examples of these diseases are obesity, osteoporosis, and acne. For example, it has also been noted that TZD promote adipogenesis in bone marrow and inhibit expression of markers of the osteoblast phenotype such as alkaline phosphatase. See, for example, Paulik, M. A. and Lenhard, J. M.,
Cell Tissue Res
., (1997), Vol. 290, pp 79-87. These effects may lead to low bone mineral density and osteoporosis. Compounds that promote osteogenesis activity may be useful in the treatment of osteoporosis. Similarly, it is known that the TZDs can promote lipid accumulation in sebocytes. See, for example, Rosenfield, R. L., Deplewski, D., Kentsis, A., and Ciletti,
N. Dermatology
, (1998), Vol. 196, pp 43-46. These effects may lead to sebocyte differentiation and acne formation. Thus, molecules that block adipogenesis in adipocytes, pre-adipocytes, bone marrow, or sebocytes may have beneficial effects in the treatment of obesity, osteoporosis, or acne.
The PPAR-gamma receptor has been found in tissues other than adipose, and it is believed that synthetic PPAR-gamma ligands and natural PPAR-gamma hormones (natural ligands) may have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. See, for example, the Schoonjans article cited above, Ricote, M. et al.,
Nature
, (1998), Vol. 391, pp 79-82, and Mueller, E. et al.,
Mol. Cell
, (1998), Vol. 1, pp 465-470.
FXR, LXR-alpha, and LXR-beta are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Repa, Joyce J. and Mangelsdorf, David J., Curr. Opin. Biotechnol. (1999), 10(6), 557-563.
There is precedent among other members of the steroid/retinoid receptor superfamily that synthetic ligands can be identified which mimic many of the beneficial effects but inhibit some of the detrimental side effects of the natural hormones. See, for example, McDonnell, D. P.,
Biochem. Soc. Trans
., (1998), Vol. 26, pp 54-60. These synthetic ligands have been given various labels, including antagonists, anti-hormones, partial agonists, selective receptor modulators, tissue selective ligands, and others. See, for example, Katzenellenbogen, J. A., O'Malley, B. W., and Katzenellenbogen, B. S.,
Mol. Endocinol
., (1996), Vol. 10, pp 119-131.
PPAR-alpha ligands of the fibrate class reduce circulating triglyceride levels and raise HDL. PPAR-alpha ligands may be useful for treatment dyslipidemia and cardiovascular disorders, see Fruchart, J.-C., Duriez, P., and Staels, B.,
Curr. Opin. Lipidol
. (1999), Vol. 10, pp 245-257. Less is known about the biology of PPAR-delta ligands, although it has been reported that they raise HDL levels, see Berger, J. et al.,
J. Biol. Chem
. (1999), Vol. 274, pp 6718-6725.
Antagonists of PPAR-alpha or PPAR-delta would be useful for characterizing the role of these receptors in mammalian physiology. For example, administration of a PPAR-alpha antagonist or PPAR-delta antagonist to a whole animal would constitute a chemical knock-out of the target receptor. Characterization of the phenotype of this chemical knock-out would indicate the role of the target receptor in mammalian physiology. This knowledge would allow the target receptor to be associated with a particular disease.
Activation of transcription by nuclear receptors involves the recruitment of coactivator proteins. Agonist ligands promote recruitment of coactivator proteins to the receptor by stabilization of the C-terminal AF-2 helix of the ligand binding domain in a conformation that forms a “charge clamp”, see Nolte et al, Nature (1998) and Shiau, A. K. et al., Cell (1998), Vol. 95, pp 927-937.
PPAR agonists such as thiazolidinediones, fibrates and fatty acids share a common binding mode to their receptors. Despite differences in the chemical structure of these agonists, the acidic headgroups of these agonist ligands accept a hydrogen bond from a tyrosine residue in the AF2 helix and/or a histidine or tyrosine residue in helix-5. These hydrogen bonds stabilize the charge clamp. This is a critical step in the activation of the receptor by an agonist ligand, see Xu et al., Mol. Cell (1999), Vol. 3, pp 397-403 and Oberfield et al., PNAS (1999), Vol. 96, pp 6102-6106. In PPAR-alpha these residues are Tyrosine 464 and Tyrosine 314, respectively, using the residue numbering in Genbank S74349 (translation G765240). In PPAR-gamma these residues are Tyrosine 473 and Histidine 323, respectively, using the residue numbering in Genbank X90563 (translation G1490313). In PPAR-delta these residues are Tyrosine 437 and Histidine 287, respectively, using the residue numbering in Genbank L07592 (translation G1902
Cobb Jeffrey Edmond
Lambert, III Millard Hurst
Milburn Michael Vance
Shearer Barry George
Brink Robert H.
SmithKline Beecham Corporation
Stockton Laura L.
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