Targeted nitroxide compounds and their use in treating ferroptosis-related diseases
Provided herein are compounds useful in the prevention or treatment of ferroptosis in a patient, and methods of preventing or treating ferroptosis, or a treating a condition or disease associated with ferroptosis, such as a patient having a neurodegenerative disease, traumatic brain injury, acute kidney disease, liver injury, ischemia/reperfusion injury, ischemic stroke, intracerebral hemorrhage, liver fibrosis, diabetes, acute myeloid leukemia, age-related macular degeneration, psoriasis, a hemolytic disorder, or an inflammatory disease.
1 . A compound having the structure:
wherein,
R 8 is an acyl group;
R 10 is (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, optionally substituted with, independently, 1, 2, or 3 F atoms;
R 11 is H;
R 12 and R 13 are, independently, (C 1 -C 6 )alkyl or (C 3 -C 8 ) cycloalkyl, that is optionally substituted with 1, 2, or 3 F atoms, or R 12 and R 13 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom;
R 14 is optionally substituted —NH—R 15 , wherein R 15 is a nitroxide -containing group; and
the double bond is cis or trans configured,
or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof.
2 . The compound of claim 1 , wherein R 15 is:
3 . The compound of claim 1 , wherein, R 8 is 9-fluorenylmethyloxy carbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzhydryloxycarbonyl (Bhoc), benzyloxycarbonyl (Cbz), O-nitroveratryloxycarbonyl (Nvoc), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), dimethoxytrityl (DMT), or monomethoxytrityl (MMT).
4 . The compound of claim 1 , wherein R 12 and R 13 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom.
5 . The compound of claim 1 , wherein R 12 and R 13 together form a cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydropyranyl ring.
6 . The compound of claim 1 , wherein R 12 and R 13 are both methyl, R 11 is H, and R 10 is (C 1 -C 4 )alkyl.
7 . The compound of claim 1 , having a structure:
8 . The compound of claim 1 , comprising one or more substituted groups, wherein each substituent of the one or more substituted groups is, independently, F, or (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, (C 3 -C 8 )cycloalkyl, or (C 2 -C 7 )cycloether that is optionally substituted with 1, 2, or 3 F atoms.
9 . The compound of claim 1 , having a structure:
10 . The compound of claim 1 , wherein R 8 is t -butyloxycarbonyl (Boc), R 10 is isobutyl, R 11 is H, and R 12 and R 13 together form a benzyl ring.
11 . A method of treating or preventing ferroptosis in a patient in need thereof, comprising administering to the patient an amount of a compound of claim 1 , effective to reduce or prevent ferroptosis in the patient, thereby reducing ferroptosis in the patient.
12 . The method of claim 11 , wherein, in the compound that is administered to the patient, R 8 is t-butyloxycarbonyl (Boc), R 10 is isobutyl, R 11 is H, and R 12 and R 13 together form a benzyl ring.
13 . The compound of claim 1 , wherein R 8 is —C(O)XR 9 , where R 9 is (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, optionally-substituted with phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, and X is —NH, —O—, or is not present.
14 . The compound of claim 1 , wherein:
R 10 is C 4 H 9 , phenyl, phenyl substituted with one F atom, or a heterocyclic 5-membered ring comprising one O atom;
R 11 is H;
R 12 and R 13 are, independently, CH 3 or benzyl, where the benzyl is optionally substituted with one F atom, or R 12 and R 13 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O atom; and
R 14 is NH—R 15 , where R 15 is
15 . The method of claim 11 , wherein the compound administered to the patient has a structure:
16 . The method of claim 11 , wherein the patient has a neurodegenerative disease, traumatic brain injury, acute kidney disease, liver injury, ischemic stroke, intracerebral hemorrhage, liver fibrosis, diabetes, acute myeloid leukemia, age-related macular degeneration, psoriasis, a hemolytic disorder, or an inflammatory disease.