Prevention and treatment of cardiovascular pathologies with tamoxifen analogues

Abstract

A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (I): wherein Z is C═O or a covalent bond; Y is H or O(C1-C4)alkyl, R1 and R2 are individually (C1-C4)alkyl or together with N are a saturated heterocyclic group, R3 is ethyl or chloroethyl, R4 is H, R5 is I, O(C1-C4)alkyl or H and R6 is I, O(C1-C4)alkyl or H with the proviso that when R4, R5, and R6 are H, R3 is not ethyl; or a pharmaceutically acceptable salt thereof, effective to elevate the level of TGF-beta to treat and / or prevent conditions such as atherosclerosis, thrombosis, myocardial infarction, and stroke is provided. Useful compounds include idoxifene, toremifene or salts thereof. Further provided is a method for identifying an agent that elevates the level of TGF-beta. Another embodiment of the invention is an assay or kit to determine TGF-beta in vitro. Also provided is a therapeutic method comprising inhibiting smooth muscle cell proliferation associated with procedural vascular trauma employing the administration of tamoxifin or structural analogs thereof, including compounds of formula (I).

Description

FIELD OF THE INVENTION [0001] This invention relates generally to the prevention and treatment of cardiovascular pathologies. More specifically, a method for treating or preventing atherosclerosis is provided. BACKGROUND OF THE INVENTION [0002] Many pathological conditions have been found to be associated with smooth muscle cell proliferation. Such conditions include restenosis, atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, smooth muscle neoplasms such as leiomyoma and leiomyosarcoma of the bowel and uterus, uterine fibroid or fibroma, and obliterative, disease of vascular grafts and transplanted organs. The mechanisms of abnormal smooth muscle cell proliferation are not yet well understood. [0003] For example, percutaneous transluminal coronary angioplasty (PTCA) is widely used as, the primary treatment modality in many patients with coronary artery disease. PTCA can relieve myocardial ischemia in patients with coronary artery disease by reduci...

AI Technical Summary

Benefits of technology

[0009] A therapeutic method for preventing or treating a cardiovascular or vascular indication characterized by a decreased lumen diameter is provided. The method comprises administering to a mammal at risk of, or afflicted with, said cardiovascular indication, a cytostatic dose of a therapeutic agent that elevates the level of TGF-beta, such as a compound of formula (I) wherein Z is C═O or a covalent bond; Y is H or O(C1-C4)alkyl, R1 and R2 are individually (C1-C4)alkyl or together with N are a saturated heterocyclic group, R3 is ethyl chloroethyl, R4 is H, R5 is I, O(C1-C4)alkyl or H and R6 is I, O(C1-C4)alkyl or H with the proviso that when R4, R5, and R6 are H, R3 is not ethyl; or a pharmaceutically acceptable salt, including mixtures thereof. The cytostatic dose is effective to directly or indirectly increase the level of TGF-beta in a mammal afflicted with said indication. Preferably, the effective amount inhibits smooth muscle cell proliferation, inhibits lipid accumulation, increases plaque stability, or any combination thereof. Thus, in this embodiment of the invention, the compound of formula (I) does not include tamoxifen, raloxifene or droloxifene. However, in other embodiments of the invention, the compound of formula(I) can include the following: R4 together with R3 is —CH2—CH2— or —S—, R5 is OH, or R4, R5, and R6 are H and R3 is ethyl.

[0010] A therapeutic method is provided for treating or preventing cardiovascular pathologies, such as conditions selected from the group consisting of atherosclerosis, thrombosis, myocardial infarction, and stroke. The method comprises the systemic or local administration of an amount of compound of formula (I). The amount is effective to increase the level of TGF-beta in said mammal afflicated with one of these conditions.

[0011] The administered compound of formula (I) can act on vascular smooth muscle cells (VSMC) to inhibit the pathological activity of these smooth muscle cells, can inhibit the activation of endothelial cells, can inhibit lipid accumulation by vessels, decrease lesion formation or development, and can increase plaque stability. Preferably, the compound significantly reduces the rate of completion of the cell cycle and cell division, and preferably is administered at cytostatic, as opposed to cytotoxic, doses. A preferred embodiment of the invention comprises treatment of atherosclerosis, wherein the compound of formulae (I), such as idoxifene or idoxifene salt, inhibits lipid accumulation by vascular smooth muscle cells and / or stabilizes an arterial lesion associated with atherosclerosis, i.e., increases plaque stability, to prevent rupture or growth of the lesion. As exemplified hereinbelow, orally administered tamoxifen significantly inhibits the formation of lipid lesions, induced by a high fat diet, in C57B16 mice and in the transgenic apo(a) mouse. The 90% reduction in lesion area and number in both of these mouse models indicates that tamoxifen affects the accumulation of lipid in the cells and stroma of the vessel wall. The inhibition of lipid accumulation and lesion development in these treated mice indicates that tamoxifen and analogs thereof, as well as compounds of formula (I) may inhibit the development of atherosclerotic lesions in humans by inhibiting lipid accumulation, in addition to decreasing smooth muscle cell proliferation.

[0031] Diabetics are prone to vascular disease. Vascular disease includes, but is not limited to, myocardial infarction, atherosclerosis, arteriolsclerosis, and small vessel disease. Moreover, the leading causes of death in diabetics are myocardial infarction and atherosclerosis. Thus, the present invention further provides a method to treat diabetics at risk of, or afflicted with, vascular disease. The method comprises the administration of an effective amount of an agent that elevates the level of TGF-beta, such as a compound of formula (I) which includes when R4 together with R3 is —CH2—CH2— or —S—, or R5 is OH, tamoxifen or a structural analog thereof. The amount is effective to directly or indirectly increase the level of TGF-beta in said diabetic. The amount administered is preferably effective to inhibit the proliferation of vascular tissue. A preferred embodiment of the invention includes the administration of idoxifene, 3-iodotamoxifen, 4-iodotamoxifen, raloxifene, droloxifene, toremifene, or a pharmaceutically acceptable salt thereof.

Problems solved by technology

Stenosis following PTCA remains a significant problem, with from 25% to 35% of the patients developing restenosis within 1 to 3 months.

Restenosis results in significant morbidity and mortality and frequently necessitates further interventions such as repeat angioplasty or coronary bypass surgery.

No surgical intervention or post-surgical treatment (to date) has proven effective in preventing restenosis.

Compounds that reportedly suppress smooth muscle proliferation in vitro may have undesirable pharmacological side effects when used in vivo.

Heparin is an example of one such compound, which reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the potential adverse side effect of inhibiting coagulation.

Low molecular weight fragments of heparin, while having reduced anti-coagulant activity, have the undesirable pharmacological property of a short pharmacological half-life.

When such an acute event occurs in the coronary artery, myocardial infarction can ensue, and in the worst case, can result in death.

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