Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-08
2001-04-10
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06214854
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new method of treatment using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting stress-activated protein kinases (SAPKs). This invention also relates to a method of treatment using compounds which are dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for treating diseases mediated by stress-activated protein kinases.
BACKGROUND OF THE INVENTION
Cells respond to extracellular stimuli by activating signal transduction pathways, which culminate in gene expression. A critical component of eukaryotic signal transduction is the activation of protein kinases, which phosphorylate a host of cellular substrates. Certain protein serine/threonine kinases transduce signals to the nucleus of cells in response to cellular stresses. These kinases are known as stress-activated protein kinases (SAPKs), or, alternately, c-Jun N-terminal (amino-terminal kinases (JNKs), and likely play a role in the genetic response of many components of the cardiovascular system to disease processes [Force, et al., Circulation Research, 78(6): 947-953 (1996)]. Stress-activated protein kinases activate genes responsible for apoptosis (cell death); SAPK activation precedes the onset of apoptosis.
Surprisingly, it has been found that carvedilol, a dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonist, inhibits stress-activated protein kinases. This inhibition means that carvedilol and related Formula I compounds are useful in treating diseases mediated by stress-activated protein kinases. Importantly, this inhibition means that carvedilol and related Formula I compounds are useful for treating SAPK-initiated apoptosis. This inhibition also means that carvedilol and related Formula I compounds are useful for treating cardiovascular diseases, such as ischemia, atherosclerosis, heart failure, and restenosis.
SUMMARY OF THE INVENTION
The present invention provides a new method of treatment using compounds which are dual non-selective &bgr;-adrenoceptor and a &agr;
1
-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting stress-activated protein kinases, in mammals, particularly humans. The present invention also provides a method of treatment using said compounds for treating diseases mediated by stress-activated protein kinases. Additionally, this invention provides a method for treating SAPK-initiated apoptosis using the compounds of Formula I. This invention further provides a method of treatment using dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists, in particular carvedilol, in the treatment of cardiovascular disorders, such as ischemia, atherosclerosis, heart failure, and restenosis following angioplasty.
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Wang Xinkang
Yue Tian-Li
Jarvis William R. A.
Kim Vickie
Kinzig Charles M.
McCarthy Mary E.
SmithKline Beecham Corporation
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