Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-26
2003-07-01
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S424000, C514S461000, C514S573000
Reexamination Certificate
active
06586457
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP
4
receptor subtype antagonist.
BACKGROUND OF THE INVENTION
A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. One of the most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, are generally chronic conditions, it is believed that appropriate therapy will typically require chronic treatment.
Normal bone physiology involves a process wherein bone tissue is continuously being turned over by the processes of modeling and remodeling. In other words, there is normally an appropriate balance between resorption of existing bone tissue and the formation of new bone tissue. The exact mechanism underlying the coupling between bone resorption and formation is still unknown. However, an imbalance in these processes is manifested in various disease states and conditions of the skeleton.
Two different types of cells called osteoblasts and osteoclasts are involved in the bone formation and resorption processes, respectively. See H. Fleisch,
Bisphosphonates In Bone Disease, From The Laboratory To The Patient,
3rd Edition, Parthenon Publishing (1997), which is incorporated by reference herein in its entirety.
Osteoblasts are cells that are located on the bone surface. These cells secrete an osseous organic matrix, which then calcifies. Substances such as fluoride, parathyroid hormone, and certain cytokines such as protaglandins are known to provide a stimulatory effect on osetoblast cells. However, an aim of current research is to develop therapeutic agents that will selectively increase or stimulate the bone formation activity of the osteoblasts.
Osteoclasts are usually large multinucleated cells that are situated either on the surface of the cortical or trabecular bone or within the cortical bone. The osteoclasts resorb bone in a closed, sealed-off microenvironment located between the cell and the bone. The recruitment and activity of osteoclasts is known to be influenced by a series of cytokines and hormones. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of systemic or localized bone disorders caused by or associated with abnormal bone resorption. However, despite the utility of bisphosphonates there remains the desire amongst researchers to develop additional therapeutic agents for inhibiting the bone resorption activity of osteoclasts.
Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. A natural prostaglandin, PGE
2
, has the following structure.
Prostaglandins such as PGE
2
are known to stimulate bone formation and increase bone mass in mammals, including man. It is believed that four different receptor subtypes, designated EP
1
, EP
2
, EP
3
, and EP
4
are involved in mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts. The major prostaglandin receptor in bone is EP
4
, which is believed to provide its effect by signaling via cyclic AMP. However, the scientific information that is currently known about the prostaglandin mediated bone effect is rather limited, because the exact mechanism of action is not known. Prostaglandins and their accosted receptors are more fully described in for example, K. Ono et al.,
Important role of EP
4
, a subtype of prostaglandin
(
PG
)
E receptor, in osteoclast
-
like cell formation from mouse bone marrow cells induced by PGE
2
, J. of Endocrinology,
158, R1-R5 (1998), C. D. Funk et al.,
Cloning and Expression of a cDNA for the Human Prostaglandin E Receptor EP! Subtype, Journal of Biological Chemistry,
vol. 268, no. 35, pp. 26767-26772 (1993), J. W. Reagan et al.,
Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP
2
Subtype, Molecular Pharmacology,
vol. 46, pp. 213-220 (1994), J. Yang et al.,
Cloning and Expression of the EP
3
-
Subtype of Human Receptors for Prostaglandin E
2
, Biochemical Biophysical Research Communication,
vol., 198, pp. 999-1006 (1994), L. Bastien et al.,
Cloning, Functional Expression and Characterization of the Human Prostaglandin E
2
Receptor EP
2
Subtype, Journal Biological Chemistry,
vol. 269, pp. 11873-11877 (1994), which are all incorporated by reference herein in their entirety.
In the present invention it is found that antagonists of the EP
4
subtype receptor are useful for inhibiting bone resorption. Without being limited by theory, it is believed that these antagonists are responsible for inhibiting the bone resorption activity of the osteoclasts.
It is an object of the present invention to provide methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP
4
receptor subtype antagonist.
It is another object of the present invention to provide methods for treating or reducing the risk of contracting a disease state or condition in a mammal in need of such treatment or prevention, comprising administering to said mammal a therapeutically effective amount of an EP
4
receptor subtype antagonist.
It is another object of the present invention to provide methods for inhibiting bone resorption in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an EP
4
receptor subtype antagonist and a bisphosphonate active.
It is another object of the present invention to provide pharmaceutical compositions comprising a therapeutically effective amount of an EP
4
receptor subtype antagonist.
It is another object of the present invention to provide pharmaceutical compositions comprising a therapeutically effective amount of an EP
4
receptor subtype antagonist and a bisphosphonate active.
It is another object of the present invention to identify EP
4
receptor subtype antagonists useful for inhibiting bone resorption.
These and other objects will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION
The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP
4
receptor subtype antagonist having an EC
50
value of from about 0.1 nanoM to about 100 microM.
In further embodiments, the present invention relates to methods for treating or reducing the risk of contracting a disease state or condition involving bone tissue in a mammal in need of such treatment or risk reduction, comprising administering to said mammal a therapeutically effective amount of an EP
4
receptor subtype antagonist.
In further embodiments, the present invention relates to methods for inhibiting bone resorption in a mammal in need th
Harada Shun-Ichi
Labelle Marc
MacHwate Mohamed
Metters Kathleen
Rodan Gideon A.
Criares Theodore J.
Daniel Mark R.
Hunter, Jr. James M.
Merck & Co. , Inc.
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