Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-08-04
2004-07-27
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S230000, C564S237000, C564S229000, C546S300000, C546S277400, C544S107000, C544S162000, C548S340100, C549S065000
Reexamination Certificate
active
06768024
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the fields of medicinal chemistry and molecular pathology and, more specifically, to novel triamine derivatives and their use as melanocortin receptor ligands and as agents for controlling obesity, sexual dysfunction or inflammation.
BACKGROUND INFORMATION
The melanocortin (MC) receptors are a group of cell surface proteins that mediate a variety of physiological effects, including regulation of adrenal gland function such as production of the glucocorticoids cortisol and aldosterone; control of melanocyte growth and pigment production; thermoregulation; immunomodulation; analgesia; obesity; feeding disorders; and sexual dysfunction. Five distinct MC receptors have been cloned and are expressed in a variety of tissues, including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue (Tatro,
Neuroimmunomodulation
3:259-284 (1996)). Three MC receptors, MCR-1, MCR-3 and MCR-4, are expressed in brain tissue (Xia et al.,
Neuroreport
6:2193-2196 (1995)).
A variety of ligands termed melanocortins function as agonists that stimulate the activity of MC receptors. The melanocortins include melanocyte-stimulating hormones (MSH) such as &agr;-MSH, &bgr;-MSH and &ggr;-MSH, as well as adrenocorticotropic hormone (ACTH). Individual ligands can bind to multiple MC receptors with differing relative affinities. The variety of ligands and MC receptors with differential tissue-specific expression likely provides the molecular basis for the diverse physiological effects of melanocortins and MC receptors. For example, &agr;-MSH antagonizes the actions of immunological substances such as cytokines and acts to modulate fever, inflammation and immune responses (Catania and Lipton,
Annals N. Y. Acad. Sci
. 680:412-423 (1993)).
More recently, the role of specific MC receptors in some of the physiological effects described above for MC receptors has been elucidated. For example, in MCR-1 is involved in pain and inflammation. MCR-1 mRNA is expressed in neutrophils (Catania et al.,
Peptides
17:675-679 (1996)). The anti-inflammatory agent &agr;-MSH was found to inhibit migration of neutrophils. Thus, the presence of MCR-1 in neutrophils correlates with the anti-inflammatory activity of &agr;-MSH.
An interesting link of MC receptors to regulation of food intake and obesity has recently been described. The brain MC receptor MCR-4 has been shown to function in the regulation of body weight and food intake. Mice in which MCR-4 has been knocked out exhibit weight gain (Huszar et al.,
Cell
88:131-141 (1997)). In addition, injecting synthetic peptides that mimic melanocortins and bind to MCR-4 into the brain of normal and mutant obese mice caused suppressed feeding (Fan et al.,
Nature
385:165-168 (1997)). These results indicate that the brain MC receptor MCR-4 functions in regulating food intake and body weight.
Due to the varied physiological activities of MC receptors, high affinity ligands of MC receptors could be used to exploit the varied physiological responses of MC receptors by functioning as potential therapeutic agents or as lead compounds for the development of therapeutic agents. Furthermore, due to the effect of MC receptors on the activity of various cytokines, high affinity MC receptor ligands could also be used to regulate cytokine activity.
Thus, there exists a need for ligands that bind to MC receptors with high affinity for use in altering MC receptor activity. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The invention provides triamine derivative melanocortin receptor ligands of the formula:
wherein R
1
to R
8
and n have the meanings provided below. The invention further provides methods of using the ligands to alter or regulate the activity of a melanocortin receptor.
REFERENCES:
patent: 3376344 (1968-04-01), Lane et al
patent: 5010175 (1991-04-01), Rutter et al.
patent: 5508432 (1996-04-01), Sugg et al.
patent: 5534530 (1996-07-01), Frehel et al.
patent: 5646140 (1997-07-01), Sugg et al.
patent: 5656648 (1997-08-01), Boigegrain et al.
patent: 5670479 (1997-09-01), Abelman et al.
patent: 5731340 (1998-03-01), Bras et al.
patent: 5739129 (1998-04-01), Aquino et al.
patent: 5795887 (1998-08-01), Aquino et al.
patent: 5859007 (1999-01-01), Aquino et al.
patent: WO 91/19735 (1991-12-01), None
patent: WO 98/34113 (1998-08-01), None
patent: WO 99/21571 (1999-05-01), None
US 5,889,182, 3/1999, Dezube et al. (withdrawn)
cas online printout of US 5670479, m=197080-83-4.*
U.S. patent application Ser. No. 09/027,108, Dooley et al., filed Feb. 20, 1998.
Catania and Lipton, “&agr;-Melanocyte-Stimulating Hormone peptides in Host responses.” Ann. N. Y. Acad. Sci., 680:412-23 (1993).
Catania et al., “The Neuropeptide &agr;-MSH has Specific Receptors on Neutrophils and reduces Chenotaxis In Vitro,”Peptides, 17:675-79 (1996).
Dorr et al., “Evaluation of melatonin—IT, a Superpotent Cyclic Melanotropic Peptide in a Pilot Phase—I Clinical Study,”Life Sciences, 50:1777-84 (1996).
Fan et al., “Role of melanocrtinergic neurons in feeding and theaqoutiobesity syndrome,” Nature, 385:165-68 (1997).
Hotamisligil and Spiegelman, “Tumor Necrosis Factor &agr;: A Key Component of the Obesity-Diabetes Link,”Diabetes, 43:1271-78 (1994).
Hotamisligil et al., “Increased Adipose Tissue Expression of Tumor Necrosis Factor-&agr;in Human Obesity and Insulin Recistance,”J. Clin. Invest.., 95:2409-15 (1995).
Hotamisligil et al., “Reduced Tyrosine Kinase Activity of the Insulin Receptor in Obesity-Diabetes,”J. Clin. Invest., 94:1543-49 (1994).
Huszar et al., “Targeted Disruption of the Melanocortin 4 Receptor Results in Obesity in Mice,”Cell, 88:131-41 (1997).
Kuby, “Immunology,” 3rded., Chapter 13 (W. H. Freeman & Co.; N. Y. 1997).
Ollmann et al., “Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein,”Science, 378:135-37 (1997).
Ostresh, “Solid-Phase Synthesis of Trisubstituted Bicyclic Guanidines via Cyclization of Reduced N-Acylated Dipeptides.”J. Org. Chem., 63:8622-23 (1998).
Platzer et al., “Up-regulation of monocytic IL-10 by tumor necrosic factor—&agr; and camp elevating drugs,”International Immunology, 7:517-23 (1995).
Star et al., “Evidence of autocrine modulation of macrophage nitric oxide synthase by &agr;—melanocyte-stimulating hormone,”Proc. Natl. Acad. Sci. USA, 92:8016-20 (1995).
Jeffrey B. Tatro, Receptor Biology of the Melanocortins, a family of Meuroimmunodulatory Peptides,Neuroimmunomodulation, 3:259-84 (1997).
Xia et al., “Expression of melanocortin 1 receptor in periaqueductal gray matter,”NeuroReport, 6:2193-96 (1995).
Gahman Timothy C.
Green Michael J.
Griffith Michael C.
Hamashin Christa
Holme Kevin R.
Barts Samuel
Law Office of David Spolter
Lion Bioscience AG
LandOfFree
Triamine derivative melanocortin receptor ligands and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Triamine derivative melanocortin receptor ligands and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Triamine derivative melanocortin receptor ligands and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3207782