MITOCHONDRIA-TARGETING PEPTIDES
Disclosed are non-natural peptides useful for the treatment and prevention of ischemia-reperfusion injury (e.g., cardiac ischemia-reperfusion injury) or myocardial infarction.
1 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier; and a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
AA 1 is selected from
AA 2 is selected from
R 1 is selected from
R 2a is selected from
R 2b is H or Me;
R 3 and R 4 are independently selected from H and (C 1 -C 6 )alkyl;
R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
R 7 is selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl;
R 8 and R 9 are independently selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl; or R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
n is 1, 2, or 3;
X is selected from
and
* denotes the point of attachment of X to R 1 .
2 . The pharmaceutical composition of claim 1 , wherein R 1 is
3 .- 9 . (canceled)
10 . The pharmaceutical composition of claim 1 , wherein R 2a is
11 . The pharmaceutical composition of claim 10 , wherein R 8 and R 9 are independently selected from H and methyl.
12 .- 13 . (canceled)
14 . The pharmaceutical composition of claim 10 , wherein R 2a is
15 . The pharmaceutical composition of claim 10 , wherein R 2a is
16 . The pharmaceutical composition of claim 1 , wherein R 2a is
17 .- 19 . (canceled)
20 . The pharmaceutical composition of claim 16 , wherein R 2a is
21 .- 23 . (canceled)
24 . The pharmaceutical composition of claim 1 , wherein AA 2 is
25 . The pharmaceutical composition of claim 24 , wherein R 7 is H.
26 .- 27 . (canceled)
28 . The pharmaceutical composition of claim 1 , wherein AA 1 is
29 .- 30 . (canceled)
31 . The pharmaceutical composition of claim 1 , wherein R 2b is H.
32 . (canceled)
33 . The pharmaceutical composition of claim 1 , wherein R 5 is H: or R 6 is H: or R 5 and R 6 are both H.
34 - 38 . (canceled)
39 . The pharmaceutical composition of claim 1 , wherein X is
40 .- 43 . (canceled)
44 . The pharmaceutical composition of claim 1 , wherein R 3 and R 4 are H.
45 .- 49 . (canceled)
50 . A method for treating or preventing a disease or condition selected from the group consisting of ischemia-reperfusion injury, myocardial infarction, hind limb ischemia, and critical limb ischemia, comprising administering to in a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
AA 1 is selected from
AA 2 is selected from
R 1 is selected from
R 2a is selected from
R 2b is H or Me;
R 3 and R 4 are independently selected from H and (C 1 -C 6 )alkyl;
R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
R 7 is selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl;
R 8 and R 9 are independently selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl; or R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
n is 1, 2, or 3;
X is selected from
and
* denotes the point of attachment of X to R 1 .
51 . The method of claim 50 , wherein the disease or condition is ischemia-reperfusion injury; and the ischemia-reperfusion injury is cardiac ischemia-reperfusion injury.
52 - 53 . (canceled)
54 . The method of claim 50 , wherein the compound is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.
55 . A method for treating or preventing renal ischemia or kidney injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
AA 1 is selected from
AA 2 is selected from
R 1 is selected from
R 2a is selected from
R 2b is H or Me;
R 3 and R 4 are independently selected from H and (C 1 -C 6 )alkyl;
R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
R 7 is selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl;
R 8 and R 9 are independently selected from H, (C 1 -C 6 )alkyl, cycloalkyl, and aryl; or R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;
n is 1, 2, or 3;
X is selected from
and
* denotes the point of attachment of X to R 1 .
56 . The method of claim 55 , wherein the renal ischemia causes uremia, acute episodes of dyspnea, hypertension, pain, weakness, nausea, leg pain, or bruits.
57 . The method of claim 55 , wherein the renal ischemia is due to acute kidney injury.
58 . The method of claim 55 , wherein the renal ischemia or kidney injury is due to, associated with, comorbid with, or related to surgery.
59 . The method of claim 58 , wherein the surgery is a heart bypass surgery.
60 . The pharmaceutical composition of claim 55 , wherein the compound is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.