US2011105602A2PendingUtilityA2
Mitochondrial Aldehyde Dehydrogenase-2 Modulators and Methods of Use Thereof
Est. expiryMar 8, 2027(~0.6 yrs left)· nominal 20-yr term from priority
A61P 9/10A61P 39/06A61P 39/02A61P 9/04A61P 9/12A61P 43/00A61P 25/28A61P 3/10A61P 25/32A61P 25/36A61P 35/00A61P 25/16C07D 317/58A61P 19/10C07D 405/12A61P 17/18A61P 21/02
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Claims
Abstract
The present invention provides compounds that function as modulators of mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity; and pharmaceutical compositions comprising the compounds. The present invention provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition. The present invention further provides assays for identifying agonists of ALDH2.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
where each of R 1 , R 2 , and R 3 is independently selected from H; a halo; a substituted or unsubstituted phenyl group; an aliphatic group, an alkyl group; a substituted alkyl group; an alkenyl group; an alkynyl group; a substituted or unsubstituted cyclic group; a substituted or unsubstituted heterocyclic group; a substituted or unsubstituted aryl group; and a substituted or unsubstituted heteroaryl group;
where A is C or S and where a=1 when A=C; and where a=2 when A=S; and
where Ar 1 and Ar 2 are independently selected from a substituted or unsubstituted aryl group;
or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof.
2 . A compound of the formula:
where X n , and X y are each independently H, C, N, O, or a halogen; where n is the integer 0 or 1; where y is the integer 0 or 1;
where . . . (dotted line) is an optional bond; where z is the integer 0, 1, or 2;
where A is C or S, and where a=1 when A=C; and where a=2 when A=S;
where Ar is an unsubstituted or substituted aryl group; and
where R 1 to R 6 is each independently selected from H; a halo (e.g., bromo, fluoro, chloro, iodo); a substituted or unsubstituted phenyl group; an aliphatic group, an alkyl group; a substituted alkyl group; an alkenyl group; an alkynyl group; a substituted or unsubstituted cyclic group; a substituted or unsubstituted heterocyclic group; a substituted or unsubstituted aryl group; and a substituted or unsubstituted heteroaryl group;
or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof.
3 . A compound of the formula:
wherein X is O or F;
. . . (dotted line) is an optional bond;
z is the integer 0, 1, or 2, with the provisos that: 1) z=0 when X=F and . . . is not a bond; and 2) when z=0, X=O, . . . is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group;
n is the integer 0 or 1;
y is the integer 0 or 1;
A=C or S, and where a=1 when A=C; and where a=2 when A=S; and
Ar is a phenyl or thiophene ring; wherein the Ar is optionally substituted at the position(s) ortho to the carbonyl or sulfonyl group by one or more substituents independently selected from methyl, halo, trifluoromethyl, or phenyl; wherein Ar is optionally substituted by a halogen meta or para to the carbonyl or sulfonyl group; and wherein, when Ar is a thiophen ring, the carbonyl or sulfonyl group is attached to a thiophene ring at the 2 or 3 position;
or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof.
4 . The compound of claim 3 , wherein A is C, and wherein Ar is a phenyl ring substituted at a position ortho to the carbonyl group.
5 . The compound of claim 4 , wherein the substitution is a halogen.
6 . A pharmaceutical composition comprising:
a) a compound of claim 1 , claim 2 , or claim 3; and b) a pharmaceutically acceptable excipient.
7 . A compound of the formula III, IV, V, VI, or VII.
8 . A pharmaceutical composition comprising:
a) a compound of claim 7; and b) a pharmaceutically acceptable excipient.
9 . A method of treating an ischemic stress condition in an individual in need thereof, the method comprising administering to the individual an effective amount of the pharmaceutical composition of claim 6 .
10 . The method of claim 9 , wherein the ischemic condition is cardiac ischemia or stroke.
11 . The method of claim 9 , wherein the pharmaceutical composition is administered by a route selected from intramuscular, intravenous, subcutaneous, and oral.
12 . The method of claim 9 , wherein the individual has an ALDH2*2 allele.
13 . A method of treating an acute or a chronic free-radical associated disease in an individual in need thereof, the method comprising administering to the individual an effective amount of the pharmaceutical composition of claim 6 .
14 . The method of claim 13 , wherein the pharmaceutical composition is administered by a route selected from intramuscular, intravenous, subcutaneous, and oral.
15 . The method of claim 13 , wherein the individual has an ALDH2*2 allele.
16 . A method of treating angina, the method comprising co-administering to an individual in need thereof a nitroglycerin compound, and a compound of any one of claims 1 - 3 in combined effective amounts to treat the angina.
17 . The method of claim 16 , wherein the nitroglycerin and the ALDH2 agonist are administered substantially simultaneously.
18 . The method of claim 16 , wherein the individual has an ALDH2*2 allele.
19 . A method of reducing a level of a compound present at a toxic level in an individual to below the toxic level, the method comprising administering to the individual an effective amount of the composition of claim 6 , wherein the compound is ethanol, methanol, ethylene glycol monomethyl ether, a vinyl chloride, a xenogenic aldehyde, a biogenic aldehyde, or a compound that give rise to a biogenic aldehyde.
20 . A method of treating a solid tumor in an individual in need thereof, the method comprising administering to the individual an effective amount of the pharmaceutical composition of claim 8 .
21 . The method of claim 20 , wherein the agent is administered as an adjuvant to a standard therapy for cancer, wherein the standard therapy for cancer is radiation therapy or chemotherapy.
22 .- 23 . (canceled)
24 . An in vitro method of identifying an agonist of a mitochondrial aldehyde dehydrogenase (ALDH2) polypeptide, the method comprising:
a) contacting a variant ALDH2 polypeptide with a substrate for ALDH2; and a test agent, wherein the variant ALDH2 comprises an E487K substitution; and b) determining the effect, if any, of the test agent on enzymatic activity of the variant ALDH2, wherein an agent that increases the enzymatic activity of the variant ALDH2 is an ALDH2 agonist.
25 . The method of claim 24 , wherein said determining step comprises measuring the level of NADH produced.
26 . The method of claim 25 , wherein said measuring comprises use of a fluorimetric assay.
27 . The method of claim 24 , wherein the variant ALDH2 comprises an amino acid sequence having at least about 80% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
28 . A method of modulating enzymatic activity of an aldehyde dehydrogenase-2 (ALDH-2) polypeptide, the method comprising contacting the ALDH-2 polypeptide with a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII.
29 . The method of claim 28 , wherein said compound increases the enzymatic activity of the ALDH-2 polypeptide.
30 . The method of claim 28 , wherein said compound decreases the enzymatic activity of the ALDH-2 polypeptide.
31 . The method of claim 28 , wherein said ALDH-2 polypeptide is in vitro.
32 . The method of claim 31 , wherein said ALDH-2 polypeptide is in a cell.
33 . The method of claim 28 , wherein said ALDH-2 polypeptide is in vivo.Join the waitlist — get patent alerts
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