Kv2.1 antagonists

Details Kv2.1 antagonists Kv2.1 antagonists

2000-06-13

2003-07-08

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S183000, C514S211090

Reexamination Certificate

active

06589934

ABSTRACT:

This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/EP98/08085 filed Dec. 16, 1998, which claims priority from GB 9726630.8 filed Dec. 18, 1997.
FIELD OF THE INVENTION
The present invention relates to methods for treating diabetes mellitus. The present invention also relates to antagonists of the potassium channel Kv2.1, methods for using and preparing the antagonists, and assays for identifying such antagonists.
BACKGROUND OF THE INVENTION
The secretion of insulin by the pancreatic &bgr;-cell plays a critical role in regulating glucose metabolism. Derangement in insulin secretion can therefore lead to impaired regulation of blood glucose, manifesting as hypoglycemia or hyperglycemia resulting in for example insulin-dependent (Type 1) diabetes mellitus or non-insulin dependent (Type 2) diabetes mellitus (NIDDM). Unlike type 1 diabetes, with NIDDM there is no autoimmune destruction of pancreatic &bgr;-cells.
The treatment of Type 2 or non-insulin dependent diabetes mellitus (NIDDM) remains unsatisfactory despite the widespread use of insulin and oral agents (sulfonylureas, biguanides and thiazolidinediones). Unfortunately the available oral agents suffer from a number of undesirable side effects which limit their usefulness in treatment of NIDDM. There is thus a clear need for the development of novel hypoglycaemic agents which may be less toxic or which suceed where others are ineffective.
&bgr;-cells located within the islets of Langerhans in the pancreas respond to an increase in glucose concentration by secreting insulin (Boyd A E III, J. Cell Biochem., 48, 234-241, 1992). The mechanism by which glucose acts as an insulin secretagogue is not completely understood, but a major component of its effect on &bgr;-cells is mediated via changes in K
+
conductance. A number of types of potassium channels are present in &bgr;-cells: these include calcium activated potassium channels, ATP sensitive potassium channels (KATP), and delayed rectifier potassium channels (Kv) (Dukes I D, Philipson L H, Diabetes, 45, 845-853, 1996). The respective roles of these potassium channels in regulating glucose—stimulated insulin secretion has not been fully elucidated.
Kv channels are multimeric membrane proteins that permit the efflux of K
+
from cells when the membrane potential is excited (i.e. depolarized) (Hille, 1993
Ionic Channels of Excitable Membranes
, 2nd ed., Sunderland M A, Sinauer Associates, 1991). A number of isoforms of Kv channels have been described, and a uniform nomenclature for their naming has been agreed (Chandy K G, Gutman G A, Trends Pharmacol. Sci., 14, 434, 1993). There are currently 8 families of mammalian delayed rectifier potassium channel genes (Kv1.x−8.x), 4 of which (Kv1.x4.x) have been demonstrated to encode functional ion channels (Chandy K G, Gutman G A in
Ligand and Voltage Gated Ion Channels
, Ed. North R A, CRC Press, 1994). The information relating to Kv channel gene expression in pancreatic &bgr;-cells is somewhat contradictory. Whereas some groups, using polymerase chain reaction (PCR), have detected Kv1.x isoforms in mouse islets and insulinoma cells (Betshlolz C, et al, FEBS Lett, 263, 121-123, 1990; Kalman K, et al, Biophys J 68:A268, 1995), and U.S. Pat. No. 5,559,009 discloses the existence of Kv1.7 message in rat pancreatic &bgr; cells and hamster insulinoma cells, others have failed to detect expression of these isoforms in &bgr;-cells, instead reporting the expression of Kv2.1 and 3.2 transcripts (Roe M W, et al, J Biol Chem 271, 32241-32246, 1996).
The present inventors have surprisingly found that antagonists of the delayed rectifier potassium channel Kv2.1 enhance insulin secretion. Accordingly, antagonists of the delayed rectifier potassium channel Kv2.1 are useful in the treatment of NIDDM.
SUMMARY OF THE INVENTION
Briefly, in one aspect, the present invention provides a method of treating NIDDM in a subject, comprising administering to the subject a therapeutically effective amount of an antagonist of the delayed rectifier potassium channel Kv2.1.
In another aspect, the present invention provides the novel compound of Formula (1), or a pharmaceutically acceptable salt or solvate thereof
wherein R represents C
1-12
alkyl, C
1-12
alkenyl, —C
y
H
2y
—R
7
or —C
y
H
2y
—O—R
7
where y is an integer from 1-6 and R
7
is hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, or a C
5-6
heterocyclic group, or R represents —C
y
H
2y
—R
9
, —C
y
H
2y
—O—R
9
, or —C
y
H
2y
—O—CH
2
—R
9
, where y is independently as defined above and R
9
is
where R
4
is hydrogen or halogen, and R
5
and R
6
independently represent hydrogen, halogen, —O—C
1-3
alkyl, or R
5
and R
6
can together form a methylenedioxy or ethylenedioxy ring;
R
1
represents
 where each R
8
is independently hydrogen, halogen, —O—C
1-3
alkyl, C
1-3
alkyl, C
1-3
fluoroalkyl, or —C(O)—R
9
where R
9
is C
4-8
alkyl, or C
3-7
cycloalkyl;
X represents O, S, or N—R
2
where R
2
is independently as defined above for R;
R
3
represents H, or C
1-3
alkyl.
As used herein terms such as alkyl, alkenyl, and the like, can be either straight chain and branched chain unless otherwise indicated.
The compounds of formula (I) are antagonists of the delayed rectifier potassium channel Kv2.1.
The compounds of the invention are useful, for example, for the treatment of NIDDM.
In another aspect, the present invention provides the use of hanatoxin or a pharmaceutically acceptable salt or solvate thereof for the treatment of NIDDM.
In another aspect, the present invention provides a method (an assay) to identify extrinsic materials possessing the ability to modulate Kv2.1 channel activity and thereby modify insulin secretion.
The following are further particular aspects of the present invention:
a) Use of a Kv2.1 antagonist for the manufacture of a medicament for the treatment of NIDDM.
b) A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy.
c) Use of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of NIDDM.
d) A method of treating NIDDM in a subject which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
e) A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable diluent or carrier.
DETAILED DESCRIPTION OF THE INVENTION
A number of toxins isolated from venomous animals are known to block potassium channels (Miller C, et al, Nature, 313, 316-318, 1985; Garcia-Calvo M, et al, J. Biol. Chem., 268, 18866-18874, 1993; Halliwell J V, et al, Proc. Natl. Acad. Sci. USA, 83, 493-497, 1986). Hanatoxin, isolated from the venom of the Chile Rose Tarantula (
Grammulosa spatulata
), has been shown to selectively block Kv2.1 channels, with minimal reported effects on representative members of Kv1, Kv3 and Kv4 delayed rectifier channels (Swartz K J, MacKinnon R, Neuron, 15, 941-949, 1995). Accordingly, hanatoxin (found in venom from the Chile Rose Tarantuala) is useful in the present invention as an antagonist of the Kv2.1 channel.
In addition to natural products, small organic molecules are known to block potassium channels. Sulfonlyureas specifically interact with KATP channels. Tetraethylammonium (TEA) and 4-aminopyridine block a wide variety of potassium channels, including those of the delayed rectifier type in the mM concentration range (Chandy K G, Gutman G A in
Ligand and Voltage Gated Ion Channels
, Ed. North R A, CRC Press, 1994). More potent potassium channel antagonists, have also been described. For instance, tedisamil (3,7-di(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo-(3.3.1)nonane) blocks Kv channels in the low &mgr;M range with no effect on inward rectifier potassium channels. Tedisamil also has effects on voltage activated s

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