Composition and methods for treating respiratory diseases

1 . A pharmaceutical composition comprising:

(i) a therapeutically effective amount of at least one ADAMTS4 inhibitor, wherein the ADAMTS4 inhibitor is:

(a) a compound represented by formula (I)

wherein R is Ome; and

R1 is

or a pharmaceutically acceptable salt thereof,

or

(b) a compound represented by formula (II)

wherein X is

or a pharmaceutically acceptable salt thereof;

and

(ii) a therapeutically effective amount of at least one antibiotic.

2 . The pharmaceutical composition of claim 1 , wherein the ADAMTS4 inhibitor is 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide, or a pharmaceutically acceptable salt thereof.

3 . The pharmaceutical composition of claim 1 , wherein the ADAMTS4 inhibitor is (S)-2-Cyclopropyl-N—(((R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)-propanamide.

4 . The pharmaceutical composition of claim 1 , wherein the antibiotic is a broad spectrum antibiotic.

5 . The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable carrier.

6 . The pharmaceutical composition of claim 1 , further comprising one or more antiviral therapeutic.

7 . The pharmaceutical composition of claim 6 , wherein the antiviral therapeutic is effective against influenza virus.

8 . A method for treating influenza A infection in a subject in need thereof, the method comprising administering to the subject:

(i) a therapeutically effective amount of at least one ADAMTS4 inhibitor, wherein the ADAMTS4 inhibitor is:

(a) a compound represented by formula (I)

wherein R is Ome; and

R1 is

or a pharmaceutically acceptable salt thereof,

or

(b) a compound represented by formula (II)

wherein X is

or a pharmaceutically acceptable salt thereof;

and

(ii) a therapeutically effective amount of at least one antibiotic.

9 . The method of claim 8 , wherein treating the infection comprises reducing at least one symptom of the infection, wherein the at least one symptom is a symptom of a secondary bacterial infection developed following a viral infection.

10 . The method of claim 8 , wherein the method comprises administering:

the antibiotic prior to administering the ADAMTS4 inhibitor;

the antibiotic subsequent to administering the ADAMTS4 inhibitor; or

the antibiotic and the ADAMTS4 inhibitor concomitantly.

11 . The method of claim 8 , further comprising administering one or more antiviral therapeutic.

12 . The method of claim 8 , wherein the method reduces inflammation, immune cell infiltration, and/or tissue damage associated with the infection.

13 . The method of claim 12 , wherein the method reduces mRNA and/or protein expression of one or more inflammatory cytokines or chemokines.

14 . The method of claim 13 , wherein the method reduces mRNA and/or protein expression of TNFA and MCP-1.

15 . The method of claim 8 , wherein the infection is a respiratory infection.