SLC26A3 inhibitors and use thereof
AssigneeThe Regents of the University of California
InventorsAlan S. Verkman, Onur Cil, Peter M. Haggie
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Abstract
Provided herein are inhibitors of SLC26A3, which is an anion (Cl−, HCO3−, oxalate) exchanger expressed in intestinal epithelial cells. SLC26A3 inhibitors have potential utility for treatment of constipation including chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), cystic fibrosis-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria and primary hyperoxalurias.
Claims12
A pharmaceutical composition comprising a physiologically acceptable excipient and a compound having one of the following structures:
A pharmaceutical composition comprising a physiologically acceptable excipient and a compound having one of the following structures:
A method for treating a condition, disease, or disorder associated with SLC26A3-mediated Cl−, HCO3−, or oxalate exchange in a subject, wherein the condition, disease, or disorder is constipation or hyperoxaluria, the method comprising administering to the subject a pharmaceutical composition comprising a physiologically acceptable excipient and a compound of Formula (I):
- or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
- R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted alkoxyalkyl, carboxyC1-C3alkyl, optionally substituted heteroarylalkyl, —S(O)2aryl (wherein aryl is optionally substituted), or optionally substituted arylalkyl;
- R2 is carboxyC1-C3alkyl;
- R3 is C1-C4 alkyl;
- and
- R4 is C1-C4 alkyl.
A method for decreasing urinary oxalate excretion in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
- or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
- R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted alkoxyalkyl, carboxyC1-C3alkyl, optionally substituted heteroarylalkyl, —S(O)2aryl (wherein aryl is optionally substituted) or optionally substituted arylalkyl;
- R2 is carboxyC1-C3alkyl;
- R3 is C1-C4 alkyl;
- and
- R4 is C1-C4 alkyl.
A method for treating a condition, disease, or disorder associated with SLC26A3-mediated Cl−, HCO3−, or oxalate exchange in a subject, wherein the condition, disease, or disorder is constipation or hyperoxaluria, the method comprising administering to the subject a pharmaceutical composition comprising a physiologically acceptable excipient and a compound of Formula (II):
- or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
- R7 is optionally substituted aryl;
- and
- R8 is optionally substituted aryl.
Dependencies are inferred from the claim text.