Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-24
2001-10-09
Jones, W. Gary (Department: 1655)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000, C514S418000, C514S419000, C514S443000, C548S250000, C548S252000, C548S254000, C548S454000, C548S506000
Reexamination Certificate
active
06300364
ABSTRACT:
TECHNICAL FIELD
This invention relates to: (1) pharmaceutical compositions having a cholesterol-lowering effect which comprises as the active ingredient a compound having a PPAR&dgr;-activating effect or a PPAR&dgr;- and PPAR&ggr;-activating effect, or a pharmaceutically acceptable salt thereof; (2) pharmaceutical compositions wherein the cholesterol-lowering effect is an LDL-cholesterol-lowering effect; (3) pharmaceutical compositions having a cholesterol-lowering effect which comprises as the active ingredient p-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenylacetic acid or a pharmaceutically acceptable salt thereof; and (4) a method for identifying a compound having a cholesterol-lowering effect characterized by measuring the peroxisome proliferation-activated receptor (PPAR)&dgr;-activating effect or the PPAR&dgr;- and PPAR&ggr;-activating effect thereof
BACKGROUND ART
An increase in blood lipid level, in particular, LDL (low density lipoprotein)-cholesterol level is considered as one of the important factors causing arteriosclerosis. LDL-cholesterol-lowering agents known hitherto include inhibitors for HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which is the rate-limiting enzyme in the cholesterol biosynthesis, and inhibitors for the intestinal reabsorption of cholesterol. For example, it is regarded that the mechanism of lowering serum LDL-cholesterol level by the administration of an HMG-COA reductase inhibitor is based on a decrease in the intracellular cholesterol and its metabolite due to the inhibition of the biosynthesis of cholesterol mainly in the liver and acceleration of the LDL receptor expression accompanying therewith (J. Lipid Res., 33, p.1569-1582, 1992).
In the phase I clinical test on simvastatin which is one of the HMG-COA reductase inhibitors, the serum cholesterol level of normal subjects showed a decrease of about 20% about 1 week after the initiation of the administration but no continuous decrease could be expected any more even though the administration was continued. It is also reported that the decrease was about 20% in a patient with hyperlipemia showing a total serum cholesterol level of 220 mg/dl or above (A. Yamamoto et al., Rinsho Iyaku (Clinical Medicine), 4(3), p.409, 1988).
On the other hand, a compound YM-16638 disclosed in an examined Japanese patent publication 63-35626, which inherently has a potent antagonism to SRS-A (slow reacting substance of anaphylaxis), is known as being useful as a preventive and a remedy for various allergic diseases (for example, bronchial asthma, urticaria), ischemic heart and brain diseases, inflammation, etc. and an antiulcer agent (Arzneim.-Forsch. Drug Res., 38(1), p.682-685, 1988; Prostaglandins Leukotrienes and Essential Fatty Acids, 36, p.43-47, 1989).
In a clinical test on this compound as an antiulcer/antiasthmatic agent, it was unexpectedly found out that this compound also showed a potent serum cholesterol-lowering effect in humans. It was also confirmed that a similar effect was observed in animal experiments (Drug Dev. Res., 38, p.86-92, 1996; an unexamined published Japanese patent application 2-215717). The above-described decrease in serum cholesterol level in the normal subjects ranged from about 26% (administration dose: 60 mg) to 41% (administration dose: 120 mg) (Drug Dev. Res., 38, p.86-92, 1996). In an initial phase II clinical test, about 80% of subjects showed a decrease of about 20 to 50%. This potent serum cholesterol-lowering effect on humans is caused not by a decrease in HDL (high density lipoprotein)-cholesterol but a significant decrease in the LDL-cholesterol apoprotein B. It is known that, on the other hand, the compound has only a weak effect of lowering serum triglyceride level (Drugs, 53(2), p.299-336, 1997).
As the results of studies on the function mechanism of the serum cholesterol-lowering effect of YM-16638, it has been clarified so far that this compound has effects of inhibiting the biosynthesis of cholesterol in the liver (Br. J. Pharmacol., 118, p.174-178, 1996), activating LDL receptor and elevating the LDL receptor gene expression level in the liver (Drug. Dev. Res., 38, p.86-92, 1996). However, the further detailed function mechanism of the compound YM-16638 achieving these effects is still unknown.
In the course of recent studies on the mechanism of the differentiation and proliferation of adipose cells, there has been proved the presence of PPAR (peroxisome proliferator-activated receptor) which is a nuclear receptor (Nature, 347, p.645-650, 1990). It has been clarified hitherto that PPAR can be roughly classified into 3 subtypes respectively called PPAR&agr;, PPAR&dgr; and PPAR&ggr; (Proc. Natl. Acad. Sci. USA, 91, p.7355-7359, 1994; Tanpakushitsu Kakusan Koso (Protein, Nucleic acid and Enzyme), 40(13), p.50-55, 1995). Furthermore, the activation of these PPAR subtypes and lipid-lowering effects of various compounds has been reported. For example, it is known that thiazolidinedione compounds, which are employed as remedies for diabetes, serve as PPAR&ggr; ligands and significantly lower the serum triglyceride level but do not lower the serum cholesterol level in human (Diabetes, 46, p.433-439, 1997; Diabetes Care, 19(2), p.151-156, 1996, 15(2), p.193-203; Diabetologia, 39, p.701-709, 1996 (Reference 1)). On the other hand, it is known that drugs of the fibrate type, which have been employed as lipid-lowering agents for a long time, serve as PPAR&agr; ligands and generally exhibit a potent effect of lowering serum triacylglycerol level in clinics (Proc. Natl. Acad. Sci. USA, 94, p.4312-4317, 1997; Drugs, 40(2), p.260-290, 1990 (Reference 2)).
Similar to these fibrate drugs, Wy 14,643 (prinixic acid) is known as a ligand specific to PPAR&agr; (EMBO J. 11, p.433-439, 1992; Arch. Biochem. Biophys., 228(1), p.185-196, 1984 (Reference 3)). However, there has never been reported the lipid-lowering effect of this compound on higher animals. Although it has been proved that prostacyclin (PGI
2
) employed as an antithrombotic agent, etc. activates neither PPAR&agr; nor PPAR&dgr; (Proc. Natl. Acad. Sci. USA, 94, p.4312-4317, 1997), it is reported that carbaprostacyclin (cPGI
2
), which is a derivative of PGI
2
, has activities of both of PPAR&agr; and PPAR&dgr; ligands. However, no detailed report has been made so far on the lipid lowering effect of this compound (J. Bio. Chem., 272(9), p.5367-5370, 1997; Proc. Natl. Acad. Sci. USA, 94, p.4312-4317, 1997 (Reference 4)).
On the other hand, Great Britain Published Patent Application GB 2292885 claims a drug for hyperlipemia wherein a substance activating NUC1 (human PPAR&dgr;) receptor is administered. However, the description on the regulation of enzyme level relating to the fatty acid oxidation disclosed in the specification of this reference relates to the metabolism of triglycerides. Namely, this reference neither discloses nor suggests any cholesterol-lowering effect.
That is, it has never been confirmed hitherto which subtype of PPAR participates in the serum cholesterol-lowering effect, though a number of findings have been made as described above.
It is expected that cholesterol-lowering agents based on the novel function mechanism in which a PPAR subtype participates would be superior in efficaciousness to the existing drugs. However, the above-described function mechanism has never been clarified hitherto and, therefore, no satisfactory drug therefor has been found out so far. Therefore, it has been keenly demanded to develop a pharmaceutically satisfactory drug having a clarified function mechanism in which a PPAR subtype participates and exerting an excellent cholesterol-lowering effect.
Disclosure of the Invention
The present inventors conducted extensive studies on the cholesterol-lowering function mechanism of the above-described compound YM-16638. As a result, they found out for the first time that this compound has an effect of activating PPAR&dgr; and PPAR&ggr;. Based on this finding and the conventional report that thiazolidinedione compounds, which are PPAR&ggr; ligand
Hashimoto Seiichi
Iizumi Yuichi
Matsuda Koyo
Nishijima Satomi
Shimokawa Teruhiko
Chakrabarti Arun Kr.
Jones W. Gary
Sughrue Mion Zinn Macpeak & Seas, PLLC
Yamanouchi Pharmaceutical Co. Ltd.
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