Novel Potassium Channel Inhibitors

Important Compound Classes

Title

Novel Potassium Channel Inhibitors

Patent Publication Number

WO2020193419

Publication Date

October 1, 2020

Priority Application

EP 19164637.1

Priority Date

March 22, 2019

Inventors

Brown, David Tristram; Christophersen, Palle; Jacobsen, Thomas Amos; Larsen, Janus S.; Poulsen, Pernille Hartveit; Stroebaek, Dorte

Assignee Company

Saniona A/S, Den.

Disease Area

Inflammatory bowel disease, hereditary xerocytosis, and acute respiratory distress syndrome (ARDS).

Biological Target

K_Ca3.1

Summary

Potassium channels play a key role in regulating the membrane potential of mammalian cells by controlling the flow of potassium ions. They can be classified as voltage activated (K_v), inward rectifier (K_IR), 2-pore (K_2P), and calcium activated (K_ca). As implied by the designation K_ca, this class of channels is activated by the presence of calcium ions. The K_Ca3.1 channel, for example, contains calmodulin regions that bind to Ca²⁺, which triggers opening of the channel and potassium ion flow. Interestingly, K_Ca3.1 has not been detected in excitable cells (e.g., neurons, smooth and striated muscle), but it is expressed by a variety of immune cells such as T-lymphocytes, B-lymphocytes, and macrophages. This channel plays a key role in maintaining membrane potential in the aforementioned cells, and dysregulation of K_Ca3.1 activity has been linked to diseases such as inflammatory bowel disease, xerocytosis erythrocytes, and acute respiratory distress syndrome (ARDS). The present patent application describes a series of K_Ca3.1 modulators that may have utility as therapies for disease and disorders associated with aberrant K_Ca3.1 activity.

Definitions

R¹⁴ is selected from the group consisting of -C(O)-C_1–8 alkyl; -C(O)-O-C_1–8alkyl; C_2–8 alkyl; -H and -S(O)₂-C_1–8 alkyl;

R³ is H, C_1–5 alkyl, or a bond;

R⁴ is H, C_1–5 alkyl, or a bond;

R⁵ is H, a bond, or C_1–8 alkyl, wherein one methylene group optionally is replaced by -O-;

R⁶ is H, a bond, or C_1–8 alkyl, wherein one methylene group optionally is replaced by -O-;

R⁷ is H, a bond, -OH, or C_1–8 alkyl, wherein one or more methylene group optionally and individually is replaced by -O- and/or substituted with =O;

R⁸ is H, a bond, -OH, or C_1–8 alkyl, wherein one or more methylene group optionally and individually is replaced by -O- and/or substituted with =O;

Any one of R³, R⁴, R⁵, R⁶, R⁷, and R⁸ optionally is linked together to form a ring;

A is a phenyl or a pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with one or more substituents R¹³ individually selected from the group consisting of halogen, -CX₃, -OCX₃, -CHX₂, -OCHX₂, -CH₂X, -OCH₂X, -CH₂CX₃, OCH₂CX₃, -C_1–8 alkyl, -OC_1–8 alkyl, -C_3–7 cycloalkyl, -OC^3–7 cycloalkyl, -CN, NO₂, -SO₂CH₃, and -SF₃; and

X is halogen;

Key Structures

Biological Assay

Erythrocyte K_Ca3.1 inhibition assay

Biological Data

Claims

20 Total claims

16 Composition of matter claims

4 Method of use claims

Recent Review Articles

• 1.Roach K. M.; Bradding P.. Ca²⁺ signalling in fibroblasts and the therapeutic potential of K_Ca3.1 channel blockers in fibrotic diseases.Br. J. Pharmacol. 2020, 177 ( (5), ), 1003–1024.
• 2.Manfroni G.; Ragonese F.; Monarca L.; Astolfi A.; Mancinelli L.; Iannitti R. G.; Bastioli F.; Barreca M. L.; Cecchetti V.; Fioretti B.. New insights on KCa3.1 channel modulation. Curr. Pharm. Des. 2020, 26 ( (18), ), 2096–2101.
• 3.Mohr C. J.; Steudel F. A.; Gross D.; Ruth P.; Lukowski R.; Mohr C. J.; Lo W. Y.; Hoppe R.; Schroth W.; Brauch H.; Huber S.. M “Cancer- Associated Intermediate Conductance Ca²⁺-Activated K⁺ Channel K_Ca3.1 Cancers 2019, 11, 1–22.

The author declares no competing financial interest.