Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment
The present invention features novel peripherally-restricted non-benzodiazipene analogs with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett syndrome, Phelan McDermid syndrome, or Fragile X syndrome, or for treating touch over-reactivity, pain, or mechanical allodynia.
1. A compound having the structure of Formula I:
wherein
A is optionally substituted C 6-10 aryl or optionally substituted heteroaryl;
Y is hydrogen, deuterium, halogen, or optionally substituted C 1-4 alkyl;
Z is oxygen, NR 3 , or CR 3 R 4 ;
R 1 is optionally substituted alkylcarboxylic acid, optionally substituted alkylcarboxylic acid ester, optionally substituted alkylcarboxylic acid amide, optionally substituted heteroalkyl, optionally substituted C 1-6 alkylamino, or C 1-6 alkyl substituted with at least one C 3-7 heterocycle comprising 1-3 nitrogen atoms, 1-2 oxygen atoms, or combinations thereof;
R 2 is optionally substituted C 1-6 alkyl;
and
each of R 3 and R 4 is, independently, hydrogen, deuterium, or optionally substituted C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound has the structure of Formula
wherein
each of X 1 and X 2 is, independently, hydrogen, deuterium, halogen, C 1-4 alkoxy, C 1-6 alkyl, CF 3 , CH 3 S, CH 3 SO 2 , NR 5 R 6 , or NO 2 ; and
each of R 5 and R 6 is, independently, hydrogen, deuterium, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, acyl, carbamate, sulfonamide, or urea;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein the compound has the structure of Formula V:
wherein
X 1 is hydrogen, deuterium, halogen, C 1-4 alkoxy, C 1-6 alkyl, CF 3 , CH 3 S, CH 3 SO 2 , or NO 2 ;
Y is hydrogen, deuterium, halogen, or C 1-4 alkyl;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , wherein the compound has the structure of Formula VII:
wherein
Z is oxygen, NH, or CH 2 ; and
R 1 is optionally substituted C 1-6 alkylamino;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable excipient.
7. A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for use.
8. The compound of claim 1 , wherein A is optionally substituted C 6-10 aryl.
9. The compound of claim 1 , wherein Y is halogen.
10. The compound of claim 1 , wherein Z is CH 2 .
11. The compound of claim 1 , wherein R 1 is optionally substituted alkylcarboxylic acid.
12. The compound of claim 3 , wherein the compound has the structure of Formula VII:
wherein
Z is oxygen, NH, or CH 2 ; and
R 1 is optionally substituted alkylcarboxylic acid;
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein X 1 is halogen.
14. The compound of claim 12 , wherein Y is halogen.
15. The compound of claim 12 , wherein Z is CH 2 .
16. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 3 .
18. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 5 .
19. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 12 .
20. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 16 .