2-beta-naphthyl-acetic acid analogs as AKR1C3 inhibitors and methods of using same
AssigneesThe Trustees of the University of Pennsylvania, Vanderbilt University
InventorsTrevor M. Penning, Adegoke Adeniji, Lawrence J. Marnett
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Abstract
The invention includes 2-β-naphthyl-acetic acid derivatives, which are selective AKR1C3 inhibitors. In certain embodiments, the compounds of the invention are (R)-naproxen analogs. The invention further includes methods of treating cancer, such as prostate cancer and/or castration-resistant prostate cancer, using at least one compound of the invention.
Claims17
A (R)-enantiomer compound of formula (Ia), or a salt or solvate thereof:
- wherein:
- R1 is selected from the group consisting of OH, —NHSO2(C1-C6 alkyl), C1-C6 alkoxy, and C3-C8 cycloalkoxy,
- wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted aryl, OH, C1-C6 alkoxy, halogen, and —CN;
- R2 is ethyl;
- and
- R4 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, —S(C1-C6 alkyl), —S(C3-C8 cycloalkyl), —S(═O)(C1-C6 alkyl), —S(═O)(C3-C8 cycloalkyl), —S(═O)2(C1-C6 alkyl), and —S(═O)2(C3-C8 cycloalkyl);
- wherein the compound is free of the corresponding (S)-enantiomer.
The compound selected from the group consisting of:
- 2(R)-(6-ethylnaphthalen-2-yl)propanoic acid;
- 2(R)-(6-ethoxynaphthalen-2-yl)propanoic acid;
- 2(R)-(6-(methylsulfinyl)naphthalen-2-yl)propanoic acid;
- 2(R)-(6-methoxynaphthalen-2-yl)-N-(methylsulfonyl)butanamide;
- and
- 2(R)-(6-methoxynaphthalen-2-yl)butanoic acid;
- or a salt or solvate thereof, or any mixtures thereof;
- wherein the compound is free of the corresponding (S)-enantiomer.
The compound 2(R)-(6-methoxynaphthalen-2-yl) butanoic acid
- or a salt or solvate thereof, or any mixtures thereof;
- wherein the compound is free of the corresponding (S)-enantiomer.
A method of treating or ameliorating prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (Ia), or a salt or solvate thereof:
- wherein:
- R1 is selected from the group consisting of OH, —NHSO2(C1-C6 alkyl), C1-C6 alkoxy, and C3-C8 cycloalkoxy,
- wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted aryl, OH, C1-C6 alkoxy, halogen, and —CN;
- R2 is ethyl;
- and
- R4 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, —S(C1-C6 alkyl), —S(C3-C8 cycloalkyl), —S(═O)(C1-C6 alkyl), —S(═O)(C3-C8 cycloalkyl), —S(═O)2(C1-C6 alkyl), and —S(═O)2(C3-C8 cycloalkyl);
- wherein the compound is free of the corresponding (S)-enantiomer.
A method of inhibiting aldo-keto reductase family 1, member C3 (AKR1C3) in a mammalian cell, the method comprising contacting the cell with an effective amount of at least one compound of formula (Ia), or a salt or solvate thereof:
- wherein:
- R1 is selected from the group consisting of OH, —NHSO2(C1-C6 alkyl), C1-C6 alkoxy, and C3-C8 cycloalkoxy,
- wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted aryl, OH, C1-C6 alkoxy, halogen, and —CN;
- R2 is ethyl;
- and
- R4 is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, —S(C1-C6 alkyl), —S(C3-C8 cycloalkyl), —S(═O)(C1-C6 alkyl), —S(═O)(C3-C8 cycloalkyl), —S(═O)2(C1-C6 alkyl), and —S(═O)2(C3-C8 cycloalkyl);
- wherein the compound is free of the corresponding (S)-enantiomer.
Dependencies are inferred from the claim text.