Drug-induced activation of the reelin signaling system
AssigneeUniversity of South Florida
InventorsEdwin John WEEBER, Qingyou LI, Melinda Marie PETERS, Hana Marie SOUEIDAN
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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.
Claims45
A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of improving cognitive function in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of increasing dendritic spine density in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of improving associative learning in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of improving spatial learning in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of improving long-term potentiation of neurons in a subject in need thereof, the method comprising administering to the subject an agonist of a lipoprotein receptor.
A method of treating a central nervous system disease or disorder by activating the Reelin signaling system in a subject in need thereof, the method comprising administering to the subject an effective amount of a small molecule agonist of a lipoprotein receptor.
A method of activating a lipoprotein receptor in a subject in need thereof, the method comprising administering to the subject a compound according to Formula I′:
- or a pharmaceutically acceptable salt thereof,
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- W is C, CH, CH2, or O;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula II:
- or a pharmaceutically acceptable salt thereof;
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- and
- m is an integer from 0 to 5;
- or Formula III:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- and
- R2 is hydrogen, halogen, hydroxyl, alkoxyl, or alkyl.
An agonist of ApoER2 or VLDLR, wherein the agonist is a compound according to Formula I′:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- W is C, CH, CH2, or O;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula II:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- and
- m is an integer from 0 to 5;
- or Formula III:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- and
- R2 is hydrogen, halogen, hydroxyl, alkoxyl, or alkyl.
A compound according to Formula I′:
- or a pharmaceutically acceptable salt thereof,
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- W is C, CH, CH2, or O;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- Q is C, CH, CH2, N, or NH;
- Z is C═O, NH, or CH2;
- Y is C═O, NH, or CH2, 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 (R2)m, wherein each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;
- or Formula II:
- or a pharmaceutically acceptable salt thereof,
- wherein each R is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- each R2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- and
- m is an integer from 0 to 5;
- or Formula III:
- or a pharmaceutically acceptable salt thereof,
- wherein each R1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;
- n is an integer from 0 to 5;
- and
- R2 is hydrogen, halogen, hydroxyl, alkoxyl, or alkyl.
Dependencies are inferred from the claim text.