SELECTIVE P2X3 MODULATORS
Provided herein are methods for the treatment of avoiding loss of taste response while treating a chronic cough patient with a selective P2X3 modulator.
1 . A method of avoiding loss of taste response while treating a chronic cough patient, the method comprising administering to the patient a therapeutically effective amount of a selective P2X3 antagonist, wherein the selective P2X3 antagonist is at least 10-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
2 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 20-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
3 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 50-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
4 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 100-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
5 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 500-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
6 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 1000-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heterotrimer receptor antagonism.
7 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 2000-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heterotrimer receptor antagonism.
8 . The method of claim 1 , wherein the selective P2X3 antagonist is at least 2700-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heterotrimer receptor antagonism.
9 . The method of any one of claims 1 - 8 , wherein the selective P2X3 antagonist is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
R 1 is selected from the group consisting of cyano, halogen, methyl, and ethyl;
R 2 is selected from the group consisting of hydrogen, halogen, methyl, and ethyl;
R 3 is selected from the group consisting of halogen, methyl, and ethyl;
R 4 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, and methoxy;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and hydroxy-C 1 -C 6 -alkyl; or
R 5 and R 6 , together with the nitrogen to which they are both attached, form a 5- or 6-member heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 4 -alkyl;
R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
R 9 is selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; and
X is selected from a bond, CH 2 , and O.
10 . The method of claim 9 , wherein R 1 is methyl.
11 . The method of claim 9 or claim 10 , wherein R 2 is hydrogen.
12 . The method of any one of claims 9 - 11 , wherein R 3 is fluoro.
13 . The method of any one of claims 9 - 12 , wherein R 4 is fluoro.
14 . The method of any one of claims 9 - 13 , wherein X is O.
15 . The method of any one of claims 9 - 14 , wherein:
the compound corresponds in structure to:
and
R 4 is selected from the group consisting of halogen, methyl, and ethyl.
16 . The method of any one of claims 9 - 15 , wherein R 5 is hydrogen.
17 . The method of any one of claims 9 - 16 , wherein R 6 is C 1 -C 6 -alkyl.
18 . The method of any one of claims 9 - 17 , wherein R 6 is methyl.
19 . The method of any one of claims 9 - 18 , wherein R 7 is hydrogen.
20 . The method of any one of claims 9 - 19 , wherein R 8 is hydrogen.
21 . The method of any one of claims 9 - 20 , wherein R 9 is C 1 -C 6 -alkoxy.
22 . The method of any one of claims 9 - 21 , wherein R 9 is methoxy.
23 . The method of any one of claims 9 - 22 , wherein the compound corresponds in structure to:
24 . The method of claim 9 , wherein the compound corresponds in structure to:
25 . The method of claim 9 , wherein the compound corresponds in structure to:
26 . The method of claim 9 , wherein the compound corresponds in structure to:
27 . The method of claim 9 , wherein the compound corresponds in structure to:
28 . The method of claim 9 , wherein the compound corresponds in structure to:
29 . The method of any one of claims 1 - 8 , wherein the selective P2X3 antagonist corresponds in structure to:
30 . The method of any one of claims 1 - 8 , wherein the selective P2X3 antagonist corresponds in structure to:
31 . The method of any one of claims 1 - 8 , wherein the selective P2X3 antagonist corresponds in structure to: