Inactivators of toxoplasma gondii ornithine aminotransferase for treating toxoplasmosis and malaria

Patent metadata

Field	Value
Publication number	US-2018098952-A1
Application number	US-201715728714-A
Country	US
Kind code	A1
Filing date	Oct 10, 2017
Priority date	Oct 10, 2016
Publication date	Apr 12, 2018
Grant date	—

Abstract

Disclosed are methods, compounds, and compositions for treating infection by an Apicomplexan parasite that include administering a compound that selectively inactivates ornithine aminotransferase of the Apicomplexan parasite. Specifically, the methods, compounds, compounds may be utilized for treating infection by Toxoplasma gondii and toxoplasmosis and for treating infection by Plasmodium falciparum and malaria. The compounds disclosed herein are observed to selectively inactivate Toxoplasma gondii ornithine aminotransferase (TgOAT) relative to human OAT and relative to human γ-aminobutyric aminotransferase (GABA-AT).

First claim

We claim:

1 . A method for treating a subject infected with an Apicomplexan parasite, the method comprising administering to the subject an effective amount of a compound that selectively inactivates ornithine aminotransferase of the Apicomplexan parasite.

2 . The method of claim 1 , wherein the Apicomplexan parasite is Toxoplasma gondii or Plasmodium falciparum.

3 . The method of claim 1 , wherein the compound has a formula:

wherein:
R 1 and R 2 are hydrogen, halo, or a C1-C6 alkyl which may be straight or branched and optionally may be substituted at one or more positions with halo; or
R 1 and R 2 together form a C1-C6 alkenyl group optionally substituted at one or more positions with halo or C1-C6 haloalkyl (e.g., trifluoromethyl); and
R 3 is hydrogen or halo.

4 . The method of claim 3 , wherein the compound has a formula:

5 . The method of claim 4 , wherein the compound has a formula:

6 . The method of claim 3 , wherein the compound has a formula:

wherein R 4 and R 5 are hydrogen, halo, or C1-C6 haloalkyl (e.g., trifluoromethyl).

7 . The method of claim 3 , wherein the compound has a formula selected from the group consisting of:

8 . The method of claim 1 , wherein the compound has a formula:

wherein:
m is 1-6;
n is 0-6; and
R 1 , R 2 , R 3 and R 4 may be the same or different and are selected from hydrogen, halo, and C1-C6 alkyl which may be straight chain or branched and may be substituted at one or more positions with halo.

9 . The method of claim 8 , wherein the compound has a formula:

10 . The method of claim 9 , wherein the compound has a formula:

11 . The method of claim 1 , wherein the compound has a formula:

wherein:
X is O, S, or N;
R 1 , R 2 , and R 3 are the same or different and are hydrogen, halo, and C1-C6 alkyl.

12 . The method of claim 11 , wherein the compound has a formula selected from the group consisting of:

13 . The method of claim 1 , wherein the compound has a formula:

wherein:
X is O, S, or N;
R 1 and R 2 are hydrogen or C1-C6 amino alkyl; and
R 3 and R 4 are hydrogen or C1-C6 carboxyl.

14 . The method of claim 13 , wherein the compound is selected from the group consisting of:

15 . The method of claim 1 , wherein the compound selectively inactivates TgOAT and k inact /K i (min −1 mM −1 ) with respect to the compound inactivating TgOAT is greater than about 1.

16 . The method of claim 1 , wherein the compound does not inactivate human OAT or inactivates human OAT and k inact /K i (min −1 mM −1 ) with respect to the compound inactivating human OAT is less than about 0.001.

17 . The method of claim 1 , wherein the compound does not inhibit human OAT or inhibits human OAT and K i with respect to the compound inhibiting human OAT is greater than about 10 mM.

18 . The method of claim 1 , wherein the compound does not inactivate human gamma-aminobutyric aminotransferase (GABA-AT) or inactivates human GABA-AT and k inact /K i (min −1 mM −1 ) with respect to the compound inactivating GABA-AT is less than about 0.001.

19 . The method of claim 1 , wherein the compound does not inhibit human GABA-AT or inhibits human GABA-AT and K i with respect to the compound inhibiting GABA-AT is greater than about 10 mM.

20 . A compound having a formula:

wherein:
m is 1-6;
n is 0-6; and
R 1 , R 2 , R 3 and R 4 may be the same or different and are selected from hydrogen, halo, and C1-C6 alkyl which may be straight chain or branched and may be substituted at one or more positions with halo.

21 . The compound of claim 20 , wherein the compound has a formula:

22 . The compound of claim 20 , wherein the compound has a formula:

23 . A pharmaceutical composition comprising the compound of claim 20 together with a pharmaceutical carrier or excipient.

Assignees

• Univ Northwestern

Inventors

• Silverman Richard B
• Le Hoang V
• Mcleod Rima L
• Hawker Dustin D

Classifications

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C12N9/1096

  transferring nitrogenous groups (2.6) · CPC title

• A61K31/03

  aromatic · CPC title

• A61K31/381

  having five-membered rings · CPC title