Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-06-14
2003-08-12
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S569000, C514S683000, C514S824000, C514S825000, C514S866000, C514S885000, C568S329000
Reexamination Certificate
active
06605639
ABSTRACT:
TECHNICAL FIELD
This invention relates to ligands of retinoid X receptor and pharmaceutical compositions for treating and/or preventing diseases which can be alleviated by the retinoid X receptor ligand (RXRL)-dependent transcriptional regulation of certain genetic information.
BACKGROUND ART
Diseases to be treated and/or prevented by use of the pharmaceutical compositions according to the present invention involve life-style related diseases. From the viewpoint of treating the life-style related diseases, there is an urgent need to develop drugs for use in the treatment of various vascular lesions causative of the onset of the life-style related diseases. Ischemic heart disease, which is prevalent when vascular lesions are present, is also referred to as coronary sclerosis. It is thought that around fifty percent of all deaths in the world are attributable this disease. Ischemic heart disease is the leading cause of death in most developed countries, and the second biggest cause of death in Japan. In addition it is estimated that the incidence of ischemic heart disease will rapidly increase in developing countries also. Major causes of ischemic heart disease, appear to include genetic factors, eating habits, stress, diabetes and hypertension. It is known that ischemic heart disease is closely related to life-style including diet. Hyperlipemia and hyperinsulinemia, which are induced by the excessive intake of high caloric diets, promote sedimentation of low density lipoproteins which are rich in cholesterol on the arterial wall. Degeneration of sedimented low density lipoproteins causes damage to the arterial wall; and leukocytes react to the damage in the arterial wall and infiltrate it to repair the lesion, resulting in chronic inflammation. Thus the mechanism of arteriosclerosis is understood to be as follows: In response to damage of arterial wall, leukocytes, which attempt to repair the damage, cause excessive inflammation which has the effect of thickening the arterial wall, resulting in a sclerosing lesion.
Typical examples of known drugs for preventing ischemic heart disease are hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. These HMG-CoA reductase inhibitors, which inhibit the biosynthesis of mevalonic acid as a rate-determining step in the biosynthesis of cholesterol, reduce the amount of cholesterol synthesized in the liver and thus lower the cholesterol content in the low density lipoprotein which is synthesized in the liver and released into the serum. That is to say, the main function of these drugs resides in inhibiting the biosynthesis of cholesterol and lowering the cholesterol content in the serum, thereby reducing the low density lipoprotein incorporated from the serum into the arterial wall depending on the concentration. Namely, these drugs exert a merely indirect and preventive effect. These HMG-CoA reductase inhibitors exhibit no effect on the sclerosing lesions associated with chronic inflammation which thickens the arterial wall in which macrophages and lymphocytes participate. Thus, it is impossible to achieve any direct therapeutic effect for healing chronic inflammation of an artery. An ideal remedy and/or preventive treatment for arteriosclerosis is a drug which shows an effect of lowering serum cholesterol level and, at the same time, a therapeutic and/or preventive effect on chronic inflammation induced by the sedimentation of cholesterol on the arterial wall. It is expected that such a drug, if any, would serve as an ideal remedy and/or preventive treatment for ischemic heart disease.
Similar to the coronary artery, the cerebral artery frequently suffers from lesions. When a cerebrovascular lesion proceeds, cerebrovascular lesions such as intracerebral bleeding or cerebral infarction are induced. Once a cerebrovascular lesion has occurred, there frequently result serious consequences such as movement disorder or intellectual disorder, even though death may be avoided. In a society where the population is aging, an increase in bedridden persons or persons suffering from senile dementia gives rise to serious social problems, and thus there is an urgent need to prevent these problems from the viewpoint of relieving the social burden of medical expenses, also. In Japan, the number of persons suffering from dementia caused by cerebrovascular dementia (i.e., partial degeneration and/or necrosis of the brain due to cerebrovascular lesions) amounts to almost 50% of the total number of persons suffering from dementia. Different from the coronary artery, the surface of the cerebral artery is coated with endothelial cells which closely overlap each other on the contact face. This coated state is referred to as tight junction. In the endothelium of the cerebral artery, endothelial cells are arranged closely without any voids. Therefore, low density lipoprotein is not incorporated into the arterial wall as in the heart. In other words, cholesterol will not induce arteriosclerosis in the cerebral artery. However, when the artery becomes enlarged due to hypertension and damage to the cerebral artery is caused, plasma components are able to penetrate the arterial wall. In response to such damage, leukocytes infiltrate the arterial wall, and as in the case of the coronary artery in the heart, the repair reaction becomes excessive. As a result, the cerebral arterial wall thickens whereby blood circulation disorders are caused; or the arterial wall becomes fragile as a result of chronic inflammation and fails to withstand blood pressure, whereby an aneurysm forms. When an aneurysm breaks, bleeding results, i.e., cerebral stroke. Thus, cerebrovascular lesion can be seen to result from chronic inflammation induced by the infiltration of leukocytes responding to repair small wounds in the artery, similar to coronary arteriosclerosis.
To prevent cerebrovascular lesions, hypotensive drugs have been employed exclusively. The effect of these hypotensive drugs resides in a lowering of blood pressure to protect vessels from excessive pressure, thereby preventing vascular damage. In other words, hypotensive drugs are employed as a preventative treatment to avoid negative effects consequent to (natural) repair of cerebral vessels. In Japan, there is a category of remedies for cerebrovascular dementia which are referred to as cerebral vasodilators, and it has been a practice to employ cerebral vasodilators such as idebenone, bifemelane hydrochloride, indeloxazine hydrochloride, nicergoline and propentofylline. As a result of clinical re-evaluation tests, however, it has been clarified that these drugs show no significant difference from placebos in therapeutic effect on negative consequences of cerebrovascular lesions. Accordingly, these drugs are no longer indicated for the treatment of the negative consequences of cerebrovascular lesions. Thus, it may be concluded that no remedy exists for the negative consequences of cerebrovascular lesions at the present time. It is expected that a drug having a hypotensive effect as well as a therapeutic effect on chronic inflammation of the cerebral artery, if any are present, would serve as an ideal remedy for cerebrovascular lesions.
As discussed above, it has been revealed that vascular lesions such as arteriosclerosis and aneurysm are induced by the repair of damage to the artery. It is known that arteriosclerosis is caused by damage to the arterial wall in a case where a narrowed artery is enlarged by inserting a balloon or a stent into it, or T lymphocytes of a host undergo a rejection reaction against an isoantigen which is present in the artery of a transplanted organ; in addition to chemical stimulus by, for example, a harmful degenerated agent such as degenerated low density lipoproteins, or under the physical stimulus of hypertension.
As examples of physical factors causative of arteriosclerosis, a treatment of inserting a balloon or a stent into a narrowed part of a coronary artery to enlarge a narrowed section (i.e., percutaneous angioplasty) may be cited. Due to its convenience and immediate effect, this treatm
Ando Kunio
Magae Junji
Tamura Gakuzo
Uchida Takafumi
Barts Samuel
Nuclear Receptor Research, Ltd.
Witherspoon Sikarl A.
LandOfFree
Ligands of nuclear receptor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Ligands of nuclear receptor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ligands of nuclear receptor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3087009