Inhibitors of kidney-type glutaminase, GLS-1

Patent metadata

Field	Value
Publication number	US-10889585-B2
Application number	US-202016735479-A
Country	US
Kind code	B2
Filing date	Jan 6, 2020
Priority date	Dec 5, 2014
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

Abstract

The present invention relates generally to glutaminase inhibitors of Formula I, Formula II, or Formula III, as well as pharmaceutical compounds containing them and methods of their use.

First claim

What is claimed:

1. A compound, or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof, wherein the compound is selected from the group consisting of:
a compound of Formula IIA:

wherein:
the dotted circle identifies an active moiety;
X is independently —CR 14a — or —N;
R 1a is independently H, —OH, —OR 14a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 14a C(O)—, R 14a OC(O)—, R 14a S(O)—, or R 14a S(O) 2 —;
R 2a , R 3a , R 4a , R 5a , and R 6a are each independently a photoreactive moiety, H, halogen, —NO 2 , —OH, —OR 14a , —SR 14a , —NH 2 , —NHR 14a , —NR 14a R 15a , R 14a C(O)—, R 14a OC(O)—, R 14a C(O)O—, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl are optionally substituted with a photoreactive moiety; or R 2a and R 3a , R 3a and R 4a , R 4a and R 5a , or R 5a and R 6a are combined to form a heterocyclic ring optionally substituted with a photoreactive moiety;
R 7a , R 8a , R 9a , and R 10a are each independently a photoreactive moiety, H, —OH, —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the aryl, heteroaryl, and aryl C 1 -C 6 alkyl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —SH, and C 1 -C 6 thioalkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl are optionally substituted with a photoreactive moiety; and
R 11a , R 11a , R 13a , R 14a , R 15a , R 16a , R 17a , R 18a , and R 19a are each independently a photoreactive moiety, H, halogen, —OH, —NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and mono or polycyclic aryl are optionally substituted with a photoreactive moiety and each one of R 11a -R 19a is optionally substituted with —NH 2 , —OH, halogen, —COOH, —NO 2 , and —CN; and

wherein the compound is optionally modified to include a tag and/or an attachment to a solid surface.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of SU-14, SU-22, and SU 24.

3. The compound according to claim 1 , wherein the compound comprises at least one photoreactive moiety.

4. The compound according to claim 3 , wherein the photoreactive moiety is selected from the group consisting of aryl azides, diazirines, and benzophenone.

5. The compound according to claim 4 , wherein the photoreactive moiety is selected from the group consisting of —N═N + ═N − ;

6. The compound according to claim 1 , wherein the compound comprises an active moiety of formula:

7. A pharmaceutical composition comprising:
a compound of claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.

8. The pharmaceutical composition of claim 7 further comprising:
a pharmaceutically acceptable carrier.

9. A method of treating a subject with a condition mediated by production of glutamate from glutamine by glutaminase GLS1, said method comprising:
selecting a subject with a condition mediated by production of glutamate from glutamine by glutaminase GLS1 and
administering to said selected subject an inhibitor of glutaminase GLS1 activity under conditions effective to treat the condition mediated by production of glutamate from glutamine, wherein the inhibitor is a compound of claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.

10. A method of reducing the production of glutamate from glutamine by glutaminase GLS1 in a sample, said method comprising:
inhibiting glutaminase GLS1 activity in the sample by a method comprising:
providing a compound and
contacting glutaminase GLS1 in the sample with the compound to reduce the production of glutamate from glutamine in the sample,
wherein the compound is a compound of claim 1 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.

11. A method of detecting glutaminase GLS1 protein in a sample, said method comprising:
providing a sample potentially containing glutaminase GLS1 protein;
contacting the sample with a compound comprising a photoreactive moiety;
exposing the compound to a light source under conditions effective to form a conjugate between the compound and glutaminase GLS1 protein, if present in the sample, through covalent modification of the photoreactive moiety; and
detecting whether any compound-glutaminase GLS1 protein conjugates are formed, wherein formation of a compound-glutaminase GLS1 protein conjugate indicates the presence of glutaminase GLS1 protein in the sample;

wherein the compound is a compound of claim 3 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.

12. A method of producing a glutaminase inhibitor-glutaminase GLS1 protein conjugate in a sample;
providing a sample containing one of (i) glutaminase GLS1 protein and (ii) a compound comprising a photoreactive moiety;
contacting the sample with the other of (i) glutaminase GLS1 protein and (ii) a compound comprising a photoreactive moiety; and
exposing the compound to a light source under conditions effective to form a conjugate between the compound and glutaminase GLS1 protein through covalent modification of the photoreactive moiety;

wherein the compound is a compound of claim 3 , or a pharmaceutically acceptable salt, ester, enol ether, enol ester, solvate, hydrate, or prodrug thereof.

13. The method according to claim 12 further comprising:
(i) detecting the compound, the conjugate, and/or the glutaminase GLS1 protein;
(ii) quantitating the amount of compound, the conjugate, and/or the glutaminase GLS1 protein present in the sample;
(iii) isolating the compound, the conjugate, and/or the glutaminase GLS1 protein from the sample;
(iv) purifying the compound, the conjugate, and/or the glutaminase GLS1 protein; or
(v) any combination thereof.

14. The compound according to claim 1 , wherein the compound is modified to include a tag and/or an attachment to a solid surface.

15. The compound according to claim 14 , wherein the compound comprises a tag.

16. The compound according to claim 15 , wherein the tag is selected from the group consisting of puri

Assignees

• Univ Cornell
• Ithaca College

Inventors

• Cerione Richard
• Cerione Kristin
• Stalnecker Clint
• Ulrich Scott

Classifications

• C07D221/18

  Ring systems of four or more rings · CPC title

• C07C237/40

  having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D277/82

  Nitrogen atoms · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title