Drug-induced activation of the Reelin signaling system

Patent metadata

Field	Value
Publication number	US-11629127-B2
Application number	US-202217723140-A
Country	US
Kind code	B2
Filing date	Apr 18, 2022
Priority date	Oct 25, 2017
Publication date	Apr 18, 2023
Grant date	Apr 18, 2023

Abstract

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR.

First claim

The invention claimed is:

1. A method of treating a disease or disorder of the central nervous system is a selected from a developmental disorder, a cognitive disorder, a degenerative disorder, a neuropsychiatric disorder, or traumatic brain injury in a subject in need thereof comprising, administering to the subject an effective amount of an agonist of a lipoprotein receptor, wherein the lipoprotein receptor is selected from ApoER2 and VLDLR, thereby improving cognitive function, increasing dendritic spine density, improving associative learning, improving special learning, or improving long-term potentiation of neurons, and wherein the agonist is a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
n is an integer from 0 to 5;
Q is C, CH, CH 2 , N, or NH;
Z is C═O, NH, or CH 2 ;
Y is C═O, NH, or CH 2 , or Z and Y may together form a bicyclic ring; and
X is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and may be unsubstituted or substituted with (R 2 ) m , wherein each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5.

2. The method of claim 1 , wherein the disease or disorder of the central nervous system is the result of a Reelin deficiency.

3. The method of claim 2 , wherein the disease or disorder of the central nervous system is selected from Lissencephaly, fragile X syndrome, William's syndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia, Alzheimer's disease, schizophrenia, bipolar disorder, neurodegeneration, traumatic brain injury, mental retardation, dementia, bipolar disorder, and stroke.

4. The method of claim 1 , wherein the lipoprotein receptor is ApoER2.

5. The method of claim 1 , wherein the lipoprotein receptor is VLDLR.

6. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the agonist is a compound of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
n is an integer from 0 to 5; and
each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; and
m is an integer from 0 to 5.

15. The method of claim 1 , wherein the agonist is a compound of Formula III:

or a pharmaceutically acceptable salt thereof,
wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
n is an integer from 0 to 5; and
each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl.

Assignees

• Univ South Florida

Inventors

• Weeber Edwin John
• Li Qingyou
• Peters Melinda Marie
• Soueidan Hana Marie

Classifications

• C07C235/24

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• C07C233/88

  having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced · CPC title

• C07D235/18

  with aryl radicals directly attached in position 2 · CPC title

• A61K31/167 Primary

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title