Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-10-22
2000-12-26
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514424, 546197, 548551, A61K 3140, A61K 31445
Patent
active
061660361
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an Lp(a) lowering agent and an apolipoprotein (a) formation suppressing agent each comprising as an effective ingredient a specific phenylcarboxylic acid derivative or salt thereof.
BACKGROUND ART
Lp(a) is a kind of lipoproteins. It is considered that apolipoprotein (a) (apo (a)) is attached, by an S--S bond, to apo B-100 which surrounds molecules analogous to low density lipoprotein (LDL), thereby circularly surrounding the particles (refer to Arteriosclerosis, 24(7.8), 369-374(1996)). As a result of investigation continued since the existence of Lp(a) was reported [Acta. Pathol. Microbiol. Scand., 59, 369-382(1963)], Lp(a) is presumed to participate in the onset of ischemic cardiac diseases or cerebral infarction. When a patient has suffered from hyperlipoproteinemia of Lp(a) in spite of being free from a factor of hypercholesterolemia, diabetes, hypertension or the like, the onset ratio of an arteriosclerotic disease is rec ognized to become markedly as one of risk factors which may cause arteriosclerosis. For example, it is reported that when the total cholesterol level in blood is normal but the Lp(a) level is high, the onset ratio of a coronary artery disease becomes high (New England J. Med., 322(1990)). In addition, it is known that the level of Lp(a) is high in Buerger's disease which is a non-arteriosclerotic lesion, which suggests the relation between them [Arteriosclerosis, 24(7.multidot.8), 369-374(1996)]. In most cases, occurrence of hyperlipoproteinemia of Lp(a) has been found to be governed by the genetic character of the patient.
In recent years, Lp(a) is found to have a fundamental structure similar to that of plasminogen and is therefore presumed to participate in the suppression of the coagulation fibrinolytic system, thus having thrombus forming action [Nature, 330, 132-137(1987)]. In addition, Lp(a) is presumed to participate in the constriction of an injured tissue in the lumen of a blood vessel by inhibiting activation of TGF-.beta. and accelerating the proliferation of endothelial cells within the blood vessel and migration of smooth muscle cells from the media into the inner membrane [J. Cell. Biol., 113, 1439-1445(1991)].
From such findings, there was a demand for the development of an agent capable of significantly lowering the Lp(a) level in blood as a remedy or preventive for arteriosclerotic diseases free from a factor of hypercholesterolemia, diabetes, hypertension or the like, a remedy or preventive for Buerger's disease, and also as anti-thrombosis and a remedy or preventive for reconstriction after PTCA.
Most of the conventional anti-hyperlipidemia agents are reported to have no apparent effects for lowering the Lp(a) level in blood. Only a nicotinic acid derivative is regarded to be effective (ARTERIOSCLEROSIS, 10(5), 672-679(1990)), but it is insufficient as a pharmaceutical, because administration at a high dose (1.5 to 2.0 g/body) is required owing to its markedly weak action and in addition, side effects such as suffusion appear.
An object of the present invention is therefore to provide an Lp(a) lowering agent which can significantly lower the Lp(a) level, is almost free from side effects and exhibits effects at a low dose. Another object of the present invention is to provide an agent for suppressing the formation of apo(a) which constitutes such Lp(a).
DISCLOSURE OF THE INVENTION
With a view to attaining the above-described objects, the present inventors have carried out an extensive investigation. As a result, paying attention to phenylcarboxylic acid derivatives and salts thereof each of which has a specific structure and is known to inhibit synthesis of cholesterol or fatty acid, the present inventors have found that such phenylcarboxylic acid derivatives and salts thereof are capable of significantly lowering the level of Lp(a), are almost free from side effects and exhibit effects at a low dose. They have also found that such derivatives and salts thereof are capable of suppressing the production of apo(
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patent: 5231184 (1993-07-01), Stokbroekx
patent: 5475118 (1995-12-01), Yano et al.
Watanabe et al., Eur. J. Med. Chem., 1994, 29, 675-686.
Powers Fiona T.
Taiho Pharmaceutical Co. Ltd.
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