Covalent, chemogenetic activators for k2p potassium channels and uses thereof
AssigneeThe Regents of the University of California
InventorsAdam R. Renslo, Daniel L. Minor, Panker E. Deal, Clifford Bryant, Xochina Cora EiHilali-Pollard, Marco Gaetano Lorenzo Lolicato
Life of this patent
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Abstract
Disclosed herein are, inter alia, activators of K2P potassium channels and pharmaceutical compositions thereof, and methods comprising their use for the treatment of diseases or adverse conditions related to low TREK family protein activity.
Claims89
A compound, or a pharmaceutically acceptable salt thereof, having the formula (I):
- wherein:
- L1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —OCX13, —OCHX12, —OCH2X1, —CN, —N3, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R2 is hydrogen, halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCHX22, —OCH2X2, —CN, —N3, —SOn2R2A, —SOv2NR2BR2C, —NHR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, NR2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is hydrogen, halogen, —CX33, —CHX32, —CH2X3, —OCX33, —OCHX32, —OCH2X3, —CN, —N3, —SOn3R3A, —SOv3NR3BR3C, —N—R3BR3C, —ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C, —N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D —NR3BOR3D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —OCX43, —OCHX42, —OCH2X4, —CN, —N3, —SOn4R4A, —SOv4NR4BR4C, —NHNR4BR4C, —ONR4BR4C, —NHC(O)NHNR4BR4C, —NHC(O)NR4BR4C, —N(O)m4, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —NR4BSO2R4A, —NR4BC(O)R4D, —NR4BC(O)OR4D, —NR4BOR4D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R5 is hydrogen, halogen, —CX53, —CHX52, —CH2X5, —OCX53, —OCHX52, —OCH2X5, —CN, —N3, —SOn5R5A, —SOv5NR5BR5C, —NHNR5BR5C, —ONR5BR5C, —NHC(O)NHNR5BR5C, —NHC(O)NR5BR5C, —N(O)m5, —NR5BR5C, —C(O)R5D, —C(O)OR5D, —C(O)NR5BR5C, —OR5A, —NR5BSO2R5A, —NR5BC(O)R5D, —NR5BC(O)OR5D, —NR5BOR5D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R6 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
- or R6 is optionally joined with L1 to form a substituted or unsubstituted heterocycloalkyl;
- R7 is independently halogen, —CX73, —CHX72, —CH2X7, —OCX73, —OCHX72, —OCH2X7, —CN, —N3, —SOn7R7A, —SOv7NR7BR7C, —NR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7BC(O)R7D, —NR7BC(O)OR7D, —NR7BOR7D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R7A, R7B, R7C, and R7D are independently hydrogen, halogen, —CF3, —Cl3, —CBr3, —CI3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- each X1, X2, X3, X4, X5, and X7 is independently halogen;
- n is an integer from 0 to 3;
- n1, n2, n3, n4, n5, and n7 are independently an integer from 0 to 4;
- m1, m2, m3, m4, m5, m7, v1, v2, v3, v4, v5, and v7 are independently 1 or 2;
- and
- R8 is a cysteine binding moiety or a serine binding moiety.
A TREK family protein or homolog thereof comprising a cysteine residue at an amino position corresponding to position 131 of TREK-1.
A method of treating a disease or adverse condition related to low TREK family protein activity in a subject in need thereof, the method comprising administering to said subject a gene editing system capable of mutating a TREK family protein to comprise a cysteine residue at an amino position corresponding to position 131 of TREK-1, and a TREK family protein agonist, wherein said TREK family protein agonist comprises a cysteine binding moiety that is capable of covalently binding said TREK family protein at said cysteine residue.
Dependencies are inferred from the claim text.