Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-11-09
2004-09-28
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S257000, C514S277000, C514S317000, C514S357000, C514S365000, C514S374000, C514S400000, C514S427000, C514S438000, C514S461000, C514S471000, C514S544000, C514S570000, C514S617000, C514S679000, C514S717000, C514S726000
Reexamination Certificate
active
06797694
ABSTRACT:
TECHNICAL FIELD
The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca
2+
activated potassium channel (IK
Ca
), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction.
BACKGROUND ART
Ion channels are transmembrane proteins, which catalyse the transport of inorganic ions across cell membranes. The ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc.
Many drugs exert their effects via modulation of ion channels. Examples are anti-epileptic compounds like Phenytoin and Lamotrigine, which block voltage dependent Na
+
-channels in the brain, anti-hypertensive drugs like Nifedipine and Diltiazem, which block voltage dependent Ca
2+
-channels in smooth muscle cells, and stimulators of insulin release like Glibenclamide and Tolbutamide, which block an ATP-regulated K
+
-channel in the pancreas.
There is a large and still growing demand for non-toxic immune-regulating agents for use in relation to e.g. organ transplantation and auto-immune diseases.
Some of the currently used immune-suppressive compounds such as Cyclosporin A and FK506 prevent immunological proliferation by inhibition of the Ca
2+
/calmodulin-dependent Ser/Thr phosphatase calcineurin. The usefulness of this class of compounds is limited by their side effects such as renal dysfunction, arterial hypertension, neurological effects (headache, insomnia, tremors, parasthesias, lethargy), gastrointestinal effects (nausea, vomiting, diarrhoea), and diabetes.
Another class of compounds comprising e.g. Azathioprine and Mizorbine interfere in a cytotoxic manner directly with the DNA-replication process. Although cytotoxicity shows some selectivity towards strongly proliferating cells such as activated T- and B-lymphocytes, complications may follow due to effects on dividing cells in the entire body, including bone marrow, hair sacs, the skin, testis, ovary and epithelia such as the airways, the intestinal tract, and the thick ascending limp of the loop of Henle's.
A fairly new approach for suppression of immune responses is to interfere with ion channels in the plasma membrane of cells in the immune system, especially the T- and B-lymphocytes. Upon exposure to antigens by antigen presenting macrophages or to mitogens such as IL-2 or IFN-&ggr;, an initial signal in the switching from the resting phase to the proliferating phase is an activation of the phosphoinositide signalling pathway resulting in an increase in the intracellular concentration of Ca
2+
([Ca
2+
]
i
) due to Ca
2+
release from intracellular stores. A sustained elevated [Ca
2+
]
i
is maintained by an increased passive influx through mitogen regulated, voltage-independent Ca-channels. This increase in [Ca
2+
]
i
, is vital for the subsequent events leading to cell proliferation and secretion of lymphokines.
In resting T- and B-lymphocytes, the [Ca
2+
] is approximately 10
7
fold higher outside versus inside the cell, and the membrane potential is negative inside, i.e. there is an inwardly directed electrochemical Ca
2+
gradient. Thus, when the Ca-channels are activated they conduct Ca into the cell. However, Ca
2+
influx via the Ca-channels, tends to reduce or even eliminate this gradient, and thus to reduce the influx. Concomitant opening of K-channels keeps the membrane potential negative, and activation of these channels is therefore essential for maintaining a large inwardly directed, electrochemical driving force for Ca
2+
.
In the presence of blockers of lymphocyte K-channels, the cells depolarise, and thereby the Ca
2+
influx necessary for the activation of the immune response is reduced.
Several types of K-channels have been described in B- and T-lymphocytes including both voltage-dependent K-channels (K
v
), and voltage-independent Ca
2+
-activated K-channels (K
Ca
). It is well established, that the K
v
-channels are activated by the Ca
2+
-induced depolarisation of the lymphocyte, and non-selective blockers of K
v
-channels are therefore quite effective immune-suppressive agents. However, these compounds in general have severe side effects due to block of re polarization in excitable tissue (seizures, myotonic runs, high blood pressure, etc.).
Considerable effort has been made into the development of immune-selective K
V
-blockers. The molecular rationale for this, has been the observation that T-lymphocytes express homomeric K
V
1.3-channels in contrast to excitable cells, which always express several heteromeric subtypes of the K
v
-channels.
A selective blocker of the K
V
1.3-homomer might therefore be an ideal, relatively non-toxic, immune-suppressive agent. Initial reports from these pharmacological programs indicate that selective K
V
1.3-blockers are very effective as anti-inflammatory agents. However, the well-known toxicity of non-selective K
V
-blockers has apparently not disappeared. An example is the potent K
v
1.3 blocker CP-339,818. This compound is also a potent blocker of K
v
1.4, a cardiac and neuronal A-type K-channel. The side-effect of this compound is predicted to be interference with the cardiac action potential (long QT-syndrome toxicity) as well as with the action potential repolarization and after hyperpolarization in neurons.
WO 97/34589 describes triaryl methane compounds that inhibit mammalian cell proliferation, inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation, and suggest the use of these compounds in abnormal cell proliferation. However, the effect of these compounds on human T cell proliferation, the use of such compounds in normal cell proliferation as immune-suppressive agents, as well as their unexpected properties when used in combination therapy has never been disclosed.
SUMMARY OF THE INVENTION
A hitherto untested alternative to the block of the voltage-dependent K-channels is a selective inhibition of the Ca
2+
-activated K-channels in T- and B-lymphocytes. These channels are directly activated by the increased [Ca
2+
]
1
which is the primary signal for lymphocyte activation. Further, contrary to K
V
-channels, these channels are voltage-independent, and therefore they do not close upon hyperpolarization, implicating that they are even more effective than K
v
channels in maintaining a large inward driving force on Ca
2+
under conditions of elevated intercellular Ca
2+
-concentrations.
Two types of Ca
2+
-activated K-channels have been described from lymphocytes: 1) Small-conductance, apamin-sensitive, Ca
2+
-activated K-channels (SK
Ca
) and 2) Intermediate-conductance, inwardly rectifying, Clotrimazole-sensitive, Ca
2+
-activated K-channels (IK
Ca
), also referred to as Gardos-channels. Resting T-lymphocytes express both SK
Ca
and IK
Ca
, whereas B-lymphocytes only express IK
Ca
.
Upon activation, prior to cell proliferation, the expression level of IK
Ca
increases approximately 30 fold in both T- and B-lymphocytes. The expression levels of both K
V
1.3 and SK
Ca
remain unchanged, indicating a major role for the IK
Ca
-channel in induction of T- and B-cell proliferation. Contrary to the SK
Ca
-channels, which are extensively expressed in CNS and heart (measured as mRNA abundance by Northern hybridisation) and in PNS, skeletal muscle, hepatocytes (measured as functional channels by electrophysiology), expression of IK
Ca
-channels have never been reported from any excitable tissue. In fact, blood cells such as erythrocytes, monocytes, lymphocytes, endothelial cells, and certain cell-lines with an epithelial ancestry, Ehrlich ascites tumour cells and HeLa cells appear to be the main source of this type of channels.
Furthermore, the very recent cloning of IK
Ca
has enabled the demonstration o
Christophersen Palle
Jensen Bo Skaaning
Olsen Soren Peter
Poseidon Pharmaceuticals A/S
Raymond Richard L.
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