Methods and compositions for improving cognition

1 . A method of improving the cognitive performance of a patient, which comprises decreasing proline transporter activity in the patient.

2 . The method of claim 1 , wherein the improved cognitive performance is enhanced learning, improved comprehension, improved reasoning, or improved short- and/or long-term memory.

3 . (canceled)

4 . (canceled)

5 . (canceled)

6 . The method of claim 1 , wherein the proline transporter is encoded by human gene SLC6A7.

7 . The method of claim 1 , wherein the activity is decreased by administering to the patient an effective amount of a compound that inhibits the proline transporter.

8 . The method of claim 7 , wherein the compound is a specific proline transporter inhibitor.

9 . The method of claim 7 , wherein the compound is of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A is an optionally substituted non-aromatic heterocycle;

each of D 1 and D 2 is independently N or CR 1 ;

each of E 1 , E 2 and E 3 is independently N or CR 2 ;

X is optionally substituted heteroaryl; Y is O, C(O), CH(OH), or CH 2 ;

each R 1 is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;

each R 2 is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;

each R A is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;

and each R B is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle.

10 . The method of claim 7 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A is an optionally substituted non-aromatic heterocycle;

each of D 1 and D 2 is independently N or CR 1 ;

each of E 1 , E 2 and E 3 is independently N or CR 2 ;

each of G 1 and G 2 are independently N or CR 3 ;

each of J 1 , J 2 and J 3 are independently N or CR 4 ; Y is O, C(O), CH(OH), or CH 2 ;

each R 1 is independently hydrogen, halogen, or (C 1-10 )alkyl;

each R 2 is independently halogen, cyano, R 2A , OR 2A , or SO 2 R 2A ;

each R 2A is independently hydrogen or (C 1-10 )alkyl optionally substituted with one or more halogens;

each R 3 is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens;

and each R 4 is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens.

11 . The method of claim 7 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.

12 . The method of claim 7 , wherein the compound is of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen, or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.

13 . The method of claim 7 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen, or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.

14 . (canceled)

15 . (canceled)

16 . A method of improving the cognitive performance of a patient, which comprises administering to the patient an effective amount of a compound that inhibits the proline transporter.

17 . The method of claim 16 , wherein the improved cognitive performance is enhanced learning, improved comprehension, improved reasoning, or improved short- and/or long-term memory.

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . The method of claim 16 , wherein the proline transporter is encoded by human gene SLC6A7.

22 . The method of claim 16 , wherein the compound is a specific proline transporter inhibitor.

23 . The method of claim 16 , wherein the compound is of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A is an optionally substituted non-aromatic heterocycle;

each of D 1 and D 2 is independently N or CR 1 ;

each of E 1 , E 2 and E 3 is independently N or CR 2 ;

X is optionally substituted heteroaryl; Y is O, C(O), CH(OH), or CH 2 ;

each R 1 is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;

each R 2 is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;

each R A is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;

and each R B is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle.

24 . The method of claim 16 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A is an optionally substituted non-aromatic heterocycle;

each of D 1 and D 2 is independently N or CR 1 ;

each of E 1 , E 2 and E 3 is independently N or CR 2 ;

each of G 1 and G 2 are independently N or CR 3 ;

each of J 1 , J 2 and J3 are independently N or CR 4 ; Y is O, C(O), CH(OH), or CH 2 ;

each R 1 is independently hydrogen, halogen, or (C 1-10 )alkyl;

each R 2 is independently halogen, cyano, R 2A , OR 2A , or SO 2 R 2A ;

each R 2A is independently hydrogen or (C 1-10 )alkyl optionally substituted with one or more halogens;

each R 3 is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens;

and each R 4 is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens.

25 . The method of claim 16 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.

26 . The method of claim 16 , wherein the compound is of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen, or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.

27 . The method of claim 16 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle;

R 2 is hydrogen or optionally substituted alkyl;

each R 3 is independently halogen, amine, hydroxy, alkoxy, or optionally substituted alkyl, aryl or heterocycle;

R 4 and R 5 are each independently hydrogen, or optionally substituted alkyl, aryl, heterocycle, alkyl-aryl or alkyl-heterocycle, or taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;

and n is 0 to 5.