US2014256767A1PendingUtilityA1
Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators
Est. expiryOct 31, 2031(~5.3 yrs left)· nominal 20-yr term from priority
C07D 207/452C07D 405/12C07D 335/06A61K 31/472A61K 31/4725C07D 217/16G01N 33/5023C07D 401/06C07D 401/14C07D 209/48
50
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Claims
Abstract
A method of identifying compounds as direct inhibitors of Keap1-Nrf2 interaction through high-throughput screening and lead development. The direct inhibitors of Keap1-Nrf2 interaction are more specific and free of various undesirable effects than existing indirect inhibitors, and are potential drug candidates of chemopreventive and therapeutic agents for treatment of various diseases or conditions involving oxidative stress and/or inflammation, including but not limited to cancers, diabetes, Alzheimer's, and Parkinson's. Novel compounds are identified and methods of preventing or treating diseases or conditions related to Keap1-Nrf2 interaction activity by use of the novel compounds identified or compositions containing such compounds are also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of preventing or treating an inflammatory disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that is a direct inhibitor of Keap1-Nrf2 protein-protein interaction, wherein said agent is a compound of formula (I):
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein:
“ ” at each occurrence is independently a single or double bond;
X at each occurrence is independently nitrogen (N) or carbon (C or CH);
Y at each occurrence is independently nitrogen (N) or carbon (C or CH);
Z is nitrogen (N) or carbon (C or CH);
L 1 is —[C(R 10 ) 2 ] i —, wherein R 10 at each occurrence is independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and i is 0, 1, 2, or 3;
L 2 is —[C(R 20 ) 2 ] j —, C 3 -C 8 cycloalkylene, C 6 -C 10 arylene, 5- to 10-membered heteroarylene, or 5- to 10-membered heterocyclylene, each optionally substituted by one to three substituents independently selected from halogen, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl, —OR 9 , and —NR a R b , wherein R 20 at each occurrence is independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and wherein j is an integer selected from 1 through 6;
R 1 is an amido or imido group, said amido or imido group comprising a group selected from unsubstituted or substituted C 6 -C 10 aryls and unsubstituted or substituted 5- to 10-membered heteroaryls;
R 2 is selected from
wherein R 2a and R 2b are each independently —OR 9 or —NR a R b ;
R 3 and R 4 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl, —CN, nitro, —COOR 11 , or —NR a R b ;
R 9 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
wherein any said cycloalkyl or heterocyclyl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, oxo, —COOR 11 , and —NR a R b ;
each said aryl or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , and —NR a R b ;
R a and R b at each occurrence are independently hydrogen or C 1 -C 6 alkyl;
R 11 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or benzyl;
R 15 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , and —NR a R b ; and
n at each occurrence is independently 0 or an integer selected from 1 to 4.
2 . The method of claim 1 , wherein the
moiety of formula (I) is selected from:
3 . The method of claim 1 , wherein the
moiety of formula (I) is
4 . The method according to any of claims 1 - 3 , wherein the
moiety of formula (I) is selected from:
5 . The method of claim 4 , wherein the
moiety of formula (I) is selected from:
wherein R 2a is OH.
6 . The method according to any of claims 1 - 5 , wherein said amido or imido of R 1 group has a formula of
wherein R 1a and R 1b are each independently hydrogen or a group selected from:
or alternatively R 1a and R 1b together form a group selected from:
wherein n at each occurrence is independently 0 or an integer from 1 to 4, and R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted phenyl, and —NR a R b .
7 . The method of claim 6 , wherein R 1a and R 1b together form a group selected from:
8 . The method of claim 7 , wherein R 1a and R 1b together form a group selected from:
9 . The method of claim 1 , wherein said agent is a compound of formula (Ia):
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein:
“ ” is a single or double bond;
L 1 is —[C(R 10 ) 2 ] i —, wherein R 10 at each occurrence is independently hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and i is 0, 1, 2, or 3;
L 2 is —[C(R 20 ) 2 ] j —, C 3 -C 8 cycloalkylene, C 6 -C 10 arylene, 5- to 10-membered heteroarylene, 5- to 10-membered heterocyclylene, wherein R 20 at each occurrence is independently hydrogen, halogen, or C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and wherein j is an integer selected from 1 through 6;
R 1 is an amido or imido group, said amido or imido group comprising a group selected from C 6 -C 14 aryls and 5- to 10-membered heteroaryls;
R 2 is —OR 9 or —NR a R b ;
R 3 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl, —CN, nitro, —COOR 11 , or —NR a R b ;
R 9 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
wherein any said cycloalkyl, or heterocyclyl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, oxo, —COOR 11 , and —NR a R b ;
each said aryl or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , and —NR a R b ;
R a and R b are each independently hydrogen or C 1 -C 6 alkyl; and
R 11 at each occurrence is independently hydrogen or C 1 -C 6 alkyl.
10 . The method of claim 9 , wherein:
“ ” is a single bond; L 1 is —(CH 2 ) i —, wherein i is 1 or 2; L 2 is —(CH 2 ) j — (j is 1, 2, or 3) or C 3 -C 8 cycloalkylene; R 1 is selected from
wherein n at each occurrence is independently 0 or an integer from 1 to 4, and R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted phenyl, and —NR a R b ;
R 2 is —OR 9 or —NR a R b ;
R 3 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, nitro, —CN, or —NR a R b ;
R 9 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or benzyl; and
R a and R b are each independently hydrogen or C 1 -C 6 alkyl.
11 . The method of claim 9 , wherein:
“ ” is a single bond; L 1 is —CH 2 — or —(CH 2 ) 2 —; L 2 is —(CH 2 ) j — (j=1, 2, or 3), cyclohexylene, or cyclopentylene; R 1 is
wherein n at each occurrence is independently 0, 1, or 2; and R 25 at each occurrence is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , phenyl, and —NR a R b ;
R 2 is —OR 9 ;
R 3 and R 4 are each hydrogen;
R 5 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, or —NR a R b ;
R 9 is hydrogen; and
R a and R b are each independently hydrogen or C 1 -C 6 alkyl.
12 . The method of claim 9 , wherein:
“ ” is a single bond; L 1 is —CH 2 — or —(CH 2 ) 2 —; L 2 is —(CH 2 ) 2 —, —(CH 2 ) 3 —,
R 1 is selected from:
R 2 is —OH, —OCH 3 , —OCH 2 Ph, or —NH 2 ;
R 3 and R 4 are each hydrogen; and
R 5 through R 8 are each independently hydrogen, F, Cl, Br, OMe, —NO 2 , or —NH 2 .
13 . The method of claim 9 , wherein:
“ ” is a single bond; L 1 is —CH 2 —; L 2 is
R 1 is selected from:
R 2 is —OH;
R 3 and R 4 are each hydrogen; and
R 5 through R 8 are each independently hydrogen, F, OMe, or —NH 2 .
14 . The method of claim 9 , wherein the agent is selected from:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof.
15 . The method of claim 9 , wherein the agent is selected from:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof.
16 . A method of preventing or treating an inflammatory disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that is a direct inhibitor of Keap1-Nrf2 protein-protein interaction, wherein said agent is a compound of formula (II):
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein:
“ ” at each occurrence is independently a single or a double bond;
X at each occurrence is independently nitrogen (N) or carbon (C or CH);
Y at each occurrence is independently nitrogen (N) or carbon (C or CH);
L 1 is
R 1 is selected from unsubstituted or substituted C 6 -C 10 aryls and unsubstituted or substituted 5- to 10-membered heteroaryls;
R 2 is
or a bioisosteric group thereof;
R 3 is hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —COOR 11 , or —NR a R b ;
wherein any said cycloalkyl, or heterocyclyl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, oxo, —COOR 11 , and —NR a R b ;
each said aryl or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , and —NR a R b ;
R a and R b are each independently hydrogen or C 1 -C 6 alkyl;
R 15 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , and —NR a R b ;
n at each occurrence is independently 0 or an integer selected from 1 to 4; and
R 11 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or benzyl.
17 . The method of claim 16 , wherein said bioisosteric group is selected from
wherein R 4 is hydrogen, halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; R 5 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and R 11 is hydrogen or C 1 -C 4 alkyl.
18 . The method of claim 16 or 17 , wherein R 1 is selected from
wherein n at each occurrence is independently 0 or an integer selected from 1 to 4; and R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted phenyl, and —NR a R b .
19 . The method according to any of claims 16 - 18 , wherein the
moiety of formula (II) has a formula selected from
wherein R 3 is hydrogen, halogen, hydroxyl, or NH 2 ; and R 4 is hydrogen or NH 2 .
20 . The method of claim 16 , wherein said agent has a formula (IIa)
wherein:
R 3 is hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —COOR 11 , or —NR a R b ;
n at each occurrence is independently 0 or an integer selected from 1 to 4;
R 15 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , and —NR a R b ;
R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted phenyl, and —NR a R b ;
R 11 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or benzyl; and
R a and R b are each independently hydrogen or C 1 -C 6 alkyl.
21 . The method of claim 16 , wherein said agent is
22 . The method according to any of claims 1 - 21 , wherein said disease or disorder is cancer, diabetes, Alzheimer's, Parkinson's, or a disease caused by oxidative stress and inflammation.
23 . A compound of formula (Ia):
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein:
“ ” is a single or double bond;
L 1 is —[C(R 10 ) 2 ] i —, wherein R 10 at each occurrence is independently hydrogen, halogen, C 1 -C 4 alkyl, and i is 1, 2, or 3;
L 2 is —[C(R 20 ) 2 ] j —, C 3 -C 8 cycloalkylene, C 6 -C 10 arylene, 5- to 10-membered heteroarylene, 5- to 10-membered heterocyclylene, wherein R 20 at each occurrence is independently hydrogen, halogen, or C 1 -C 4 alkyl, and j is an integer selected from 1 through 6;
R 1 is selected from
wherein n at each occurrence is independently 0 or an integer from 1 to 4, and R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted C 6 -C 10 aryl, and —NR a R b ;
R 2 is —OR 9 or —NR a R b ;
R 3 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, —CN, nitro, —COOR 11 , or —NR a R b ;
R 9 at each occurrence is independently hydrogen or C 1 -C 6 alkyl;
wherein any said cycloalkyl, or heterocyclyl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, oxo, —COOR 11 , and —NR a R b ;
each said aryl or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , and —NR a R b ;
R a and R b are each independently hydrogen or C 1 -C 6 alkyl; and
R 11 at each occurrence is independently hydrogen or C 1 -C 6 alkyl; provided that the compound of formula (I) is not
24 . The compound of claim 23 , wherein:
“ ” is a single bond; L 1 is —(CH 2 ) i —, wherein i is 1 or 2; and L 2 is —(CH 2 ) j — (j is 1, 2, or 3) or C 3 -C 8 cycloalkylene.
25 . The compound of claim 24 , wherein: R 1 is selected from
wherein n at each occurrence is independently 0 or an integer from 1 to 4, and R 25 at each occurrence is independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , —CONR a R b , substituted or unsubstituted phenyl, and —NR a R b ;
R 2 is —OR 9 or —NH 2 ;
R 3 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, nitro, —CN, or —NR a R b ;
R 9 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, or benzyl; and
R a and R b are each independently hydrogen or C 1 -C 6 alkyl.
26 . The compound of claim 23 , wherein:
“ ” is a single bond; L 1 is —CH 2 — or —(CH 2 ) 2 —; L 2 is —(CH 2 ) j — (j=1, 2, or 3), cyclohexylene, or cyclopentylene; R 1 is selected from
wherein n at each occurrence is independently 0, 1, or 2; and R 25 at each occurrence is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, nitro, —COOR 11 , phenyl, and —NR a R b ;
R 2 is —OR 9 ;
R 3 and R 4 are each hydrogen;
R 5 through R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, or —NR a R b ;
R 9 is hydrogen; and
R a and R b are each independently hydrogen or C 1 -C 6 alkyl.
27 . The compound of claim 23 , wherein:
“ ” is a single bond; L 1 is —CH 2 — or —(CH 2 ) 2 —; L 2 is —(CH 2 ) 2 —, —(CH 2 ) 3 —,
R 1 is selected from:
wherein n is 0 or 1; and R 25 is selected from H, F, Cl, Br, -Ph, —NO 2 , —NH 2 , C 1 -C 4 alkyl, and —CO 2 H;
R 2 is —OH, —OCH 3 , —OCH 2 Ph, or —NH 2 ;
R 3 and R 4 are each hydrogen; and
R 5 through R 8 are each independently hydrogen, F, Cl, Br, OMe, —NO 2 or —NH 2 .
28 . The compound of claim 23 , wherein:
“ ” is a single bond; L 1 is —CH 2 —; L 2 is
R 1 is selected from:
R 2 is —OH;
R 3 and R 4 are each hydrogen; and
R 5 through R 8 are each independently hydrogen, F, —OMe, or —NH 2 .
29 . The compound of claim 23 , selected from the group consisting of:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof.
30 . A substantially enantiomerically pure compound selected from the group consisting of:
or a prodrug, a pharmaceutically acceptable salt or solvate thereof.
31 . The substantially enantiomerically pure compound of claim 30 , selected from:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof.
32 . A compound according to any of claims 23 - 31 for use in the treatment of an inflammatory disease or disorder associated with Keap1-Nrf2 interaction.
33 . A composition comprising a compound according to any of claims 23 - 31 , and a pharmaceutically acceptable carrier.
34 . A method of treating a disease or disorder associated with Keap1-Nrf2 interaction, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any of claims 23 - 31 or the composition of claim 33 .
35 . The method of claim 34 , wherein the disease or disorder is cancer, diabetes, Alzheimer's, Parkinson's, or a disease caused by oxidative stress and inflammation.
36 . Use of a compound according to any of claims 23 - 31 in the manufacture of a medicament for treatment of an inflammatory disease or disorder associated with Keap1-Nrf2 interaction.
37 . The use of claim 36 , wherein the disease or disorder is cancer, diabetes, Alzheimer's, Parkinson's, or a disease caused by oxidative stress and inflammation.
38 . A method of identifying a lead or candidate compound useful for developing small-molecule therapeutic agents for treatment of inflammatory diseases or conditions associated with Keap1-Nrf2 protein-protein interaction, comprising screening a plurality of compounds against a Keap1-Nrf2 interaction target, the method comprising the steps of:
(a) incubating a library of compounds with a Keap1 Kelch domain in a culture medium in parallel at a pre-determined concentration of the compounds for a period of time; (b) measuring concentrations of unbound Keap1 Kelch domain for the compounds screened using SA chip immobilized with biotin-16mer Nrf2 peptide (300 RU); (c) calculating percent inhibitions of the compounds to the Keap1-Nrf2 interaction based on the concentrations of unbound Keap1 Kelch domain; and (d) selecting compounds having a percent inhibition of at least 20%, at least 30%, at least 40%, or at least 50% at a pre-determined concentration of the compounds in the range of between 1 μM and 50 μM.
39 . The method of claim 38 , wherein said pre-determined concentration of the compounds is 5 μM and 50 μM, and the percent inhibition is at least 50%.
40 . The method of claim 38 or 39 , further comprising steps of:
(e) evaluating selected compounds from step (d) in cell-based ARE b-lactamase reporter assay using CellSensor HepG2 cell line; and
(f) selecting compounds from step (e) exhibiting an ARE-inducing activity in the CellSensor® ARE-b1a Hep G2 cell line with an EC 50 of less than 20 μM using 150 μM tBHQ as 100%.
41 . A compound selected from the group consisting of:
or an analog, a stereoisomer, a prodrug, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of an inflammatory disease or disorder associated with Keap1-Nrf2 interaction or for use as a direct inhibitor to Keap1-Nrf2 protein-protein interaction.
42 . The compound of claim 41 , wherein the disease or disorder is cancer, diabetes, Alzheimer's, Parkinson's, or a disease caused by oxidative stress and inflammation.Join the waitlist — get patent alerts
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