COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE USING A COMBINATION THERAPY OF SMALL MOLECULE INHIBITORS OF C-C CHEMOKINE RECEPTOR TYPE 9 (CCR9) AND ANTI-ALPHA4BETA7 INTEGRIN BLOCKING ANTIBODIES
Provided herein are compositions, methods and kits for treating inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis in a mammal in need thereof. The method include administering to a subject with IBD a combination therapy containing a therapeutically effective amount of a chemokine receptor 9 (CCR9) inhibitor compound and a therapeutically effective amount of an anti-α4β7 integrin antibody such as vedolizumab. Also provided herein is a kit containing the CCR9 inhibitor compound and anti-α4β7 integrin antibody.
1 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
(i) a therapeutically effective amount of a CCR9 chemokine receptor inhibitor
or a pharmaceutically acceptable salt thereof;
(ii) a therapeutically effective amount of an anti-α4β7 integrin blocking antibody; and
(iii) instructions for effective administration.
2 . The kit of claim 1 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).
3 . The kit of claim 1 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab.
4 . The kit of claim 1 , wherein the CCR9 chemokine receptor inhibitor is a compound having formula (I) or a salt thereof:
where
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl, and;
R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or
R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;
R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;
R 4 is H or F;
R 5 is H, F, Cl, or —CH 3 ;
R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or substituted or unsubstituted C 1-8 aminoalkyl;
R a is H or substituted or unsubstituted C 1-8 alkyl;
where R 5 and R 6 may together form a carbocyclic ring;
L is a bond, —CH 2 —, or —CH(CH 3 )—;
each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected from the group consisting of N, N—O, and —CR 8 —; where at least one and not more than two of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are N or N—O;
R 8 is each independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and
R 20 and R 21 are each independently H, or substituted or unsubstituted C 1-8 alkyl.
5 . The kit of claim 4 , where one of A 1 or A 2 is N or N—O, and the remaining of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are —CR 8 —, where each R 8 is selected independently.
6 . The kit of claim 1 , wherein the CCR9 chemokine receptor inhibitor is a compound having formula (II) or a salt thereof:
where
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl;
R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or
R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;
R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;
R 4 is H or F;
R 5 is H, F, Cl, or —CH 3 ;
R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy;
R a is H or substituted or unsubstituted C 1-8 alkyl;
where R 5 and R 6 may together form a carbocyclic ring;
L is a bond, —CH 2 —, or —CH(CH 3 )—; and
Z is selected from the group consisting of:
and N-oxides thereof;
where the Z group may be unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;
each R 8 is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and
R 20 and R 21 are each independently H, substituted or unsubstituted C 1-8 alkyl.
7 . The kit of claim 6 , wherein the inhibitor is a compound having formula (IIIa) or (IIIb) or a salt thereof:
where
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl;
R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or
R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;
R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;
R 4 is H or F;
R 5 is H, F, Cl, or —CH 3 ;
R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy;
R a is H or substituted or unsubstituted C 1-8 alkyl;
or where R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;
each R 8 is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R 20 and R 21 are each independently H, or substituted or unsubstituted C 1-8 alkyl; and
n is 0, 1, 2 or 3.
8 . The kit of claim 7 , wherein the compound is selected from the group consisting of
9 . The kit of claim 1 , wherein the CCR9 chemokine receptor inhibitor is
10 . The kit of claim 1 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for sequential administration or concomitant administration.
11 . The kit of claim 10 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for concomitant administration.
12 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
(i) a therapeutically effective amount of vercirnon or a pharmaceutically acceptable salt thereof;
(ii) a therapeutically effective amount of an anti-α4β7 integrin blocking antibody; and
(iii) instructions for effective administration.
13 . The kit of claim 12 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for sequential administration or concomitant administration.
14 . The kit of claim 13 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for concomitant administration.
15 . The kit of claim 12 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).
16 . The kit of claim 12 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab.
17 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
(i) a therapeutically effective amount of a CCR9 chemokine receptor inhibitor or a pharmaceutically acceptable salt thereof;
(ii) a therapeutically effective amount of an anti-TNFα blocking antibody; and
(iii) instructions for effective administration.
18 . The kit of claim 17 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC).
19 . The kit of claim 17 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab.
20 . The kit of claim 17 , wherein the CCR9 chemokine receptor inhibitor is