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Selective Modulators of PPAR-gamma and Methods for the Use Thereof (S95031.pdf)

Inventors
Ron Evans and Barry Forman

Applications
Cardiovascular, Obesity, Drug Discovery and Development
Use of PPAR-gamma-selective compounds for the treatment of obesity and diabetes.

Because obesity is associated with the development of serious medical conditions, including noninsulin-dependent diabetes mellitus, hypertension, coronary artery disease, hyperlipidemias and certain malignancies, it is important that compounds to control adiposity are identified. The conversion of fibroblasts into cells of the adipose lineage is induced by expression of the orphan nuclear receptor PPAR-gamma. Accordingly, an endogenous PPAR-gamma ligand may be an important regulator of adipogenesis. This invention reveals PPAR-gamma as a drug target and relates to a class of compounds which are capable of selectively modulating processes mediated by PPAR-gamma. The identification of such compounds makes possible the selective intervention in PPAR-gamma mediated pathways, without exerting inadvertent effects on pathways mediated by other PPAR isoforms..

References
Cell 1995 Dec 1;83(5):803-12.

Patent Status:
U.S. Patent No. 6,830,882 issued December 14, 2004

License Terms:
Exclusive or Nonexclusive licenses available

Reference_Number: S95031
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Use of RAR Antagonists as Modulators of Hormone Mediated Processes (S96028.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Cardiovascular, Obesity. Drug Discovery and Development
RAR Antagonists are capable of modulating processes mediated by other members of the steroid/thyroid hormone receptor superfamily, including permissive receptors such as PPARs.

Retinoic acid receptor (RAR) antagonists are capable of modulating processes mediated by non-RAR members of the steroid/thyroid hormone receptor superfamily including permissive receptors such as PPARs (e.g., PPAR-alpha, PPAR-delta and PPAR-gamma). It has been discovered that RAR antagonists, in combination with agonists for members of the steroid/thyroid hormone receptor superfamily, are capable of inducing and/or enhancing processes mediated by such members. Such compositions will modulate the activity of permissive heterodimers. Permissive heterodimeric members of the steriod/thyroid hormone receptor superfamily include PPAR:RXR, LXR:RXR, NGFI-B:RXR, NURR1:RXR, FXR:RXR, BXR:RXR, SXR:RXR. For example, PPAR regulates genes involved in fatty acid degradation. This is blocked by retinoid agonists. In contrast, an RAR antagonist can stimulate PPAR signalling. Accordingly, a composition composed of an RAR antagonist and a PPAR agonist could represent a unique approach to treat PPAR controlled syndromes such as cardiovascular disease, hyperlipidemia, obesity or insulin resistance which are characterized by altered levels of fatty acids or their metabolites..

References
No publications to date

Patent Status:

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Kir Channel Modulators (S06017.pdf)

Inventors
Scott Pegan, Paul Slesinger, Senyon Choe, Prafulla Aryal

Applications
Cardiology, CNS, Screening, Drug Discovery
Methods and materials for modulating Kir channel activity and identification of related compounds.

Inwardly-rectifying potassium (Kir) channel proteins are involved in a diverse range of biological processes, including regulation of cardiac and neurological functions. In contrast to voltage-gated potassium channels that allow large fluxes of K+ ions out of the cell when opened during membrane electrical activity, Kir channels allow fluxes of K+ ions out of the cell at resting membrane potentials, maintaining excitability. In addition, Kir channels are modulated by alcohols. Aberrant activity of Kir channels has been linked to a variety of endocrine, cardiac, and neurological disorders. In particular, mutations in Kir channel proteins have been implicated in analgesia, cardiac arrhythmias and Andersen's Syndrome. Consequently, new compounds discovered using the methods described could be therapeutically useful to control heart dysfunctions and neurological disorders such as epilepsy, as well as for developing novel analgesics. Scientists at the Salk Institute have recently determined the structure of the cytoplasmic domain of the Kir2 channel protein, and discovered that a small alcohol-like molecule, known as MPD, binds to a specific location within the protein domain. Additional studies indicate that low concentrations of MPD activate the related Kir3 subfamily of channel proteins. The Kir channel three-dimensional structure has been used to design mutants for characterizing the pharmacological properties of the alcohol pocket. This discovery provides a stereochemical basis for the systematic design, synthesis, and screening of related alcohol-like compounds in order to identify those that modulate Kir channel activities. The technology disclosed in the pending patent includes the elucidated structure of a representative Kir channel protein in combination with an alcohol and methods for identifying agents that modulate Kir channel activity and predicting whether an agent is capable of binding to a Kir channel..

References
Biochemistry. 46: 5315-5322 (2007)

Patent Status:
U.S. Patent Application filed 6/20/2007

License Terms:
Exclusive and Non-Exclusive Licenses available

Reference_Number: S06017
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Corticotropin Releasing Factor-Binding Protein (CRF-BP) (S54426.pdf)

Inventors
Wylie Vale, Ellen Potter, Dominic Behan, Wolfgang Fischer, Elizabeth Linton, and Philip Lowry

Applications
CNS, Cardiovascular, Oncology, Obesity, Drug Discovery and Development
Proteins capable of binding and modulating the biological effect of CRF

The invention relates to CRF-BPs which are capable of binding to and modulating the biological effect of CRF and which have therapeutic applications. These CRF-BPs can be administered therapeutically to bind to and inactivate CRF thereby reducing high ACTH levels in mammals caused by excess CRF and can be used to treat Cushing's Disease, and the like. These CRF-BPs are also useful in combating pituitary tumors that produce CRF. Moreover, they can be used to reduce pituitary ACTH secretion and hence reduce cortisol levels under any condition in which they are abnormally high, such as during chronic stress or in patients afflicted with anorexia nervosa or alcoholism. CRF-BP or fragments thereof and/or antibodies to the proteins may be employed in diagnostic assays to determine the levels of CRF, CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. The DNA or subsequence thereof can be used as probes for genetic material in certain assays. The anti-CRF-BP antibodies are also useful to purify the CRF-BP protein and to modulate the biological effect of the CRF-BPs proteins. CRF-BPs can also be employed to screen for inhibitors which may be used to treat obesity and Alzheimer's disease..

References
Nature 349:423-426 (January 1991)
Genomics 16:63-68 (1993)

Patent Status:
U.S. Patent No. 5,733,790 issued March 31, 1998
U.S. Patent No. 5,910,428 issued June 8, 1999
Numerous Foreigns

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S54426
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Urocortin (S96012.pdf)

Inventors
Wylie Vale, Joan Vaughan, Cynthia Donaldson, Kathy Lewis, Paul Sawchenko, Jean Rivier, Marilyn Perrin

Applications
CNS, Cardiovascular
A native mammalian peptide with potent hypotensive activity used as a therapeutic or target

The invention relates to Urocortin, a native mammalian peptide generally related to Urotensin I and Corticotropin Releasing Factor (CRF). Urocortin or analogs thereof not only are potent hypotensive agents but they have additional pharmacological and physiological properties over and beyond those of heretofore known CRFs. Pharmaceutical compositions of Urocortin can be used to lower blood pressure or increase coronary flow, decrease swelling and inflammation, improve memory and learning performance, and elevate mood. The invention also relates to competitive binding assays which are particularly useful for screening candidates for new drugs..

References
Nature 378: 287-292 (1995)
Endocrinology 137: 2167-2170 (1996)
Science 273: 1561-1564 (1996)

Patent Status: