Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Patent
1995-11-30
1998-04-21
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
568729, A61K 3105, C07C 3904
Patent
active
057418217
DESCRIPTION:
BRIEF SUMMARY
This application is 371 of PCT/AU94/00297 which is now published as WO 94/28886 on Dec. 22, 1994.
TECHNICAL FIELD
The present invention relates to the use of naturally occurring phenolic compounds and related synthetic compounds in the treatment or prophylaxis of cardiovascular disease and to novel phenolic compounds and the use thereof in the treatment or prophylaxis of cardiovascular disease.
BACKGROUND ART
Cardiovascular disease is a serious health problem and a major cause of death in Australia and most developed countries. It has been reported that calcium is central to cardiovascular function, in that the calcium ion controls the contraction of heart muscle and the tone of blood vessels. Certain drugs have been used to increase intracellular calcium in order to stimulate the failing heart (cardiotonic agents). The major drugs used for congestive heart failure in the past are derived from digitalis, found naturally in plants such as foxglove. Their action to raise intracellular calcium, however, is indirect, as they inhibit Na.sup.+,K.sup.+ -ATPase which results in an increase in intracellular Na.sup.+, which then in turn stimulates the inflow of extracellular calcium and in turn stimulates the failing heart. These drugs are not ideal as they are toxic at doses only slightly higher than therapeutic cardiotonic concentrations. There has been an active search for alternative cardiotonic agents in recent years and there is still a need for effective drugs to treat and prevent various aspects of cardiovascular disease.
Ca.sup.2+ has a variety of functions in most animal cells. The concentration of free calcium ion (Ca.sup.2+) in the cytoplasmic space acts as an intracellular messenger in both electrical and non-electrical excitable cells. The important role of Ca.sup.2+ is in relation to cellular contraction, and proliferation especially contraction and relaxation of the heart.
The movement of Ca.sup.2+ across cells is regulated by number of mechanisms. If there are means that can pharmacologically manipulate these processes then the level of free intracellular Ca.sup.2+ may be altered, resulting in a change in cellular response.
There are number of calcium pools which contribute to the concentration of Ca.sup.2+ in the cytoplasmic space. Two major important pools are namely, the extracellular pool and the internal store, the so-called sarcoplasmic reticulum (SR) store.
The entry of extracellular Ca.sup.2+, down its electrochemical gradient, not only raises the level of intracellular Ca.sup.2+ but also initiates the release of Ca.sup.2+ from the SR store. This phenomenon explains the rapid contraction of cells. The rise of intracellular Ca.sup.2+ is compensated by a number of mechanisms to remove Ca.sup.2+ from the cytoplasmic space, either by extruding the Ca.sup.2+ out of the cell through the Ca.sup.2+ pump, which is biochemically coupled to Ca.sup.2+ -ATPase, and the Ca.sup.2+ /Na.sup.+ exchanger, and by sequestering of Ca.sup.2+ back into the SR store through SR Ca.sup.2+ -ATPase. These removal mechanisms are energy-dependent processes that utilise ATP as the energy source.
The present inventors have found that a range of naturally occurring phenols and related synthetic compounds manipulate the plasma membrane Ca.sup.2+ -ATPase process named, hereafter, as the plasma membrane Ca.sup.2+ -ATPase. It is anticipated that they may also alter the SR Ca.sup.2+ -ATPase, given the similarity of this enzyme to this plasma membrane Ca.sup.2+ -ATPase. Compounds discovered can inhibit the plasma membrane Ca.sup.2+ -ATPase causing an increased level of free Ca.sup.2+ inside cell. At the same time, some of the compounds may be chosen to stimulate the SR Ca.sup.2+ -ATPase, thereby increasing Ca.sup.2+ uptake into the internal SR store and making more Ca.sup.2+ available for release from the SR. The overall effect of these compounds is to increase the rate of contraction as well as the force of contraction of the heart cells, and particular of the failing heart.
It has been reported that a number of reagents in
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Duke Colin Charles
Li Qian
Roufogalis Basil Don
Aulakh Charanjit S.
Rotman Alan L.
The University of Sydney
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