DREADD actuators

Patent metadata

Field	Value
Publication number	US-11739063-B2
Application number	US-201916968437-A
Country	US
Kind code	B2
Filing date	Feb 6, 2019
Priority date	Feb 7, 2018
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

Disclosed is a compound of formula (I) in which R1, R2, and R3 are as described herein. Also provided are pharmaceutical compositions comprising the compound of formula (I) and methods of using the compound of formula (I), including a method of treating a disease or disorder and a method for effectuating a G-protein coupled receptor (GPCR)-mediated response in a subject.

First claim

The invention claimed is:

1. A method of reducing locomotor activity in a subject in need thereof comprising administering a compound of, or a pharmaceutically acceptable salt thereof, to the subject, wherein the compound is of formula (III)

wherein R 1 is fluoro, bromo, or iodo, and R 3 is methyl or ethyl, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the subject expresses a DREADD-modified human muscarinic G-protein coupled receptor (GPCR), wherein the modified receptor is selected from the group consisting of hM3Dq and hM4Di.

3. A method for effectuating a G-protein coupled receptor (GPCR)-mediated response in a subject, the method comprising:
administering to the subject a vector encoding a DREADD-modified human muscarinic GPCR (hM-DREADD), wherein the modified receptor is selected from the group consisting of hM3Dq and hM4Di, to express the modified receptor, and
administering a compound, or a pharmaceutically acceptable salt thereof, to the subject, wherein the compound is of formula (III)

wherein R 1 is fluoro, bromo, or iodo, and R 3 is methyl or ethyl, or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , further comprising:
imaging the subject by positron emission tomography.

5. The method of claim 4 , further comprising:
comparing the level of expression of the modified receptor as determined by positron emission tomography to a control, and
adjusting the amount of the compound, or a pharmaceutically acceptable salt thereof, that is administered to the subject.

6. The method of claim 3 , further comprising:
imaging the subject by magnetic resonance imaging (MRI), and optionally magnetic resonance spectroscopy.

7. The method of claim 6 , further comprising:
comparing the level of expression of the modified receptor as determined by MRI to a control, and
adjusting the amount of the compound, or a pharmaceutically acceptable salt thereof, that is administered to the subject.

8. The method of claim 4 , wherein R 1 is fluoro.

9. The method of claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The method of claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The method of claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein the bromo substituent is bromine-76 ( 76 B).

13. The method of claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein the iodo substituent is iodine-124 ( 124 I).

15. The method of claim 4 , wherein the fluoro substituent is fluorine-18 ( 18 F).

16. The method of claim 4 , wherein the method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound, or a pharmaceutically acceptable salt of the compound, to the subject.

Assignees

• Us Health
• Univ Johns Hopkins

Inventors

• Bonaventura Jordi
• Gomez Juan Luis
• Horti Andrew
• Hu Feng
• MICHAELIDES Michael
• Pomper Martin
• Sanchez-Soto Marta

Classifications

• C07D403/04

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D243/38 Primary

  [b, e]- or [b, f]-condensed with six-membered rings · CPC title

• A61K49/10

  Organic compounds · CPC title

• A61K31/5517 Primary

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title