Small molecule inhibition of sulfotransferase SULT1A3

Patent metadata

Field	Value
Publication number	US-12291504-B2
Application number	US-201917299733-A
Country	US
Kind code	B2
Filing date	Dec 10, 2019
Priority date	Dec 10, 2018
Publication date	May 6, 2025
Grant date	May 6, 2025

Abstract

Provided herein are small molecule compounds and methods inhibiting human sulfotransferase 1A3 (SULT1A3) using these small molecule compounds. Methods of manufacturing and treatment are also disclosed.

First claim

The invention claimed is:

1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

is a naphthalene or a quinoline;
X is selected from a bond and an optionally substituted alkyl or alkene;
Y is selected from —OR′, —CONR′ 2 , —COOR′ and optionally substituted heteroaryl;
R′ is H or an optionally substituted alkyl;
Z is independently selected from H, optionally substituted alkyl, and —X-Y, or two Z together form an optionally substituted cycloalkyl, wherein when Z 1 and Z 2 are both H, then Y is heteroaryl, or wherein Z 1 and Z 2 are not both H;
a is 0 or an integer of 1-4; and
wherein the compound of formula (I) is selected from:

2. A compound having the structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from a —C 0 -C 6 alkyl or a —C 2 -C 6 alkene;
Y is selected from —OR', —COOR′, —CONR′ 2 , and heteroaryl;
R′ is H or C 1 -C 6 alkyl;
Z 1 is selected from H and —OR′; and
Z 2 is selected from H, —C 1 -C 6 alkyl, and —C 0 -C 6 -COOR′, or
Z 1 and Z 2 together form a substituted cycloalkyl,
wherein when Z 1 and Z 2 are both H, then Y is heteroaryl and
wherein the compound of formula (II) is selected from:

3. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

4. A method of inhibiting SULT1A3 in a subject in need thereof, comprising administering a compound of claim 1 , or a composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier to the subject.

5. The method of claim 4 , wherein the subject is a human.

6. A method inhibiting SULT1A3 in a cell, comprising contacting a cell with a compound of claim 1 .

7. The method of claim 6 , wherein the cell is a mammalian cell, and optionally wherein the mammalian cell is a human cell.

8. A method of inhibiting the activity of SULT1A3, comprising providing a SULT1A3 enzyme, and contacting the SULT1A3 enzyme with a compound of claim 1 .

9. The method of claim 8 , wherein:
(a) the contacting of SULT1A3 is performed in vitro; or
(b) the contacting of SULT1A3 is performed in vivo.

10. A method of prolonging therapeutic efficacy of a catecholic drug or lowering the effective concentration of a catecholic drug in a subject in need, comprising administering a compound of claim 1 , or a composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier, to the subject.

11. A method of preventing metabolization of dopamine in a subject in need comprising administering a compound of claim 1 , or a composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier, to the subject.

12. A method of retarding tumor progression of hepatocellular carcinoma in a subject in need comprising administering a compound of claim 1 , or a composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier, to the subject.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education
• Albert Einstein College Medicine

Inventors

• Deiters Alexander
• Darrah Kristie E
• Cacace Mary Frances
• Cook Ian
• Leyh Thomas
• Wang Ting

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D249/06

  with aryl radicals directly attached to ring atoms · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D215/04

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms · CPC title