HYPDH inhibitors and methods of use for the treatment of kidney stones
AssigneesWake Forest University Health Sciences, The UAB Research Foundation
InventorsW. Todd Lowther, Ross P. Holmes, Daniel Yohannes
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Abstract
Provided herein are compounds of Formula (I), Formula (II), and Formula (III), and compositions comprising the same, as well as methods of use thereof for controlling or inhibiting the formation of calcium oxalate kidney stones, inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting hydroxyproline dehydrogenase (HYPDH).
Claims18
A method of inhibiting the formation of oxalate kidney stones, comprising:
- administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:
- wherein:
- X is O, or CRxRy, wherein Rx and Ry are each;
- n is 0, 1, 2, 3, 4, 5 or 6;
- R1 is carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each hydroxy;
- and
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- or a pharmaceutically acceptable salt thereof.
A method of inhibiting the production of glyoxylate and/or oxalate in a subject in need thereof, comprising:
- administering to said subject a therapeutically effective amount of a compound of Formula I:
- wherein:
- X is O, S or CRxRy, wherein Rx and Ry are each H;
- n is 0, 1, 2, 3, 4, 5 or 6;
- R1 is carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each hydroxy;
- and
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- or a pharmaceutically acceptable salt thereof.
A method of inhibiting hydroxyproline dehydrogenase (HYPDH) in a subject in need thereof, comprising:
- administering to said subject a therapeutically effective amount of a compound of Formula I:
- wherein:
- X is O, S or CRxRy, wherein Rx and Ry are each H;
- n is 0, 1, 2, 3, 4, 5 or 6;
- R1 is carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each hydroxy;
- and
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.