US2020354336A9PendingUtilityA9
Treatment of Lung Diseases Using Pharmaceutical Agents that Eliminate Senescent Cells
Est. expiryAug 11, 2037(~11.1 yrs left)· nominal 20-yr term from priority
Inventors:Nick VlahakisScott A. ArmstrongJamie DananbergRyan HudsonAnne-Marie BeausoleilNathaniel DavidRemi-Martin Laberge
A61P 35/00C07D 401/12A61P 11/00C07D 207/36A61K 31/496A61P 43/00C07F 9/09A61K 31/661A61P 19/02C07F 9/650952A61P 27/00C07D 401/10C07D 401/14C07D 207/34A61P 9/10C07D 207/337C07F 9/65583C07D 403/10
60
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Claims
Abstract
This invention is based on the discovery that many lung diseases associated with aging are mediated at least in part by cells bearing a senescent phenotype. Senescent cells accumulate with age, and express factors that contribute to the pathophysiology of age related conditions. The severity of age-related conditions typically correlates with the abundance of senescent cells: thus, clearing senescent cells can help abrogate the condition: providing symptomatic relief, and potentially inhibiting disease progression. In accordance with this invention, a family of Bcl protein inhibitors has been developed for the treatment of lung diseases. These senolytic agents have an appropriate dose and specificity profile to be effective in the clinical management of previously intractable pulmonary diseases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to Formula (II):
wherein:
X 1 is —Cl;
X 2 is —COOH or —SO 2 CH 3 ;
X 3 is —SO 2 CF 3 , —SO 2 CH 3 , or —NO 2 ;
X 5 is —F or —H;
R 1 is —CH(CH 3 ) 2 ;
R 2 is —CH 3 ;
R 3 and R 4 are both —H;
n is 2;
R 6 is selected from —OH, —OR 7 ,
and
R 7 is —PO(OH) 2 ,
or a salt or a stereoisomer thereof.
2 . The compound of claim 1 , wherein X 2 is —COOH.
3 . The compound of claim 1 , wherein X 2 is —SO 2 CH 3 .
4 . The compound of claim 1 , wherein X 3 is —SO 2 CF 3 .
5 . The compound of claim 1 , wherein X 3 is —SO 2 CH 3 .
6 . The compound of claim 1 , wherein X 3 is —NO 2 .
7 . The compound of any of claims 1 to 6 , wherein X 5 is —F.
8 . The compound of any of claims 1 to 6 , wherein X 5 is —H.
9 . The compound of any of claims 1 to 8 , wherein X 6 is —OH.
10 . The compound of any of claims 1 to 8 , wherein X 6 is —OR 7 .
11 . The compound of any of claims 1 to 8 , wherein X 6 is
12 . The compound of any of claims 1 to 8 , wherein X 6 is
13 . The compound of any of claims 1 to 8 , wherein X 6 is
14 . The compound of any of claims 1 to 13 , wherein the carboxyl group in X 2 is phosphorylated.
15 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
16 . The compound of any preceding claim, which has pro-apoptotic activity.
17 . The compound of any preceding claim, which specifically kills senescent cells compared with non-senescent cells, said senescent cells being defined as non-cancerous cells that express p16.
18 . The compound of any preceding claim, which specifically kills cancer cells compared with non-cancer cells of the same tissue type.
19 . The compound of any preceding claim, which has an IC 50 for Bcl-xL of 1 nM or less.
20 . The compound of any preceding claim, which has an IC 50 for Bcl-2 of 10 nM or less.
21 . The compound of any preceding claim, which has an IC 50 for Bcl-xL of 1 nM or less and an IC 50 for Bcl-2 of 10 nM or less.
22 . A pharmaceutical composition comprising a compound according to any preceding claim in a pharmaceutically compatible excipient.
23 . A method of selectively removing senescent cells and/or cancer cells from a mixed cell population or tissue, comprising contacting a cell, a cell population or a tissue with a compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22 .
24 . A method of treating a senescence related condition in a tissue in a subject, wherein the senescence related condition is characterized as being caused or mediated at least in part by senescent cells, or is characterized as having an overabundance of senescent cells in or around the tissue, in comparison with unaffected tissue, the method comprising:
administering to a tissue of a subject in need thereof, an amount of a compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22 that is effective to selectively remove senescent cells from the tissue, thereby relieving or ameliorating one or more signs or symptoms of a senescence related condition in the subject.
25 . A unit dose of a pharmaceutical composition comprising:
an amount of a compound that inhibits Bcl function configured for use in the treatment of a senescence associated condition that is caused or mediated at least in part by senescent cells, wherein the compound is a compound according to any of claims 1 to 21 , wherein the pharmaceutical composition contains a formulation of the compound configured for administration to a target tissue in a subject that manifests the senescence associated condition, and wherein the formulation and the amount of the compound in the unit dose configure the unit dose to be effective in selectively removing senescent cells in or around the tissue in the subject, thereby decreasing the severity of one or more signs or symptoms of the condition without causing adverse effects in the subject when administered to the tissue as a single dose.
26 . The unit dose of claim 25 , packaged with an informational insert describing the use and attendant benefits of the drugs in treating the senescent cell associated condition.
27 . A compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 24 for use in selectively eliminating senescent cells from a tissue or mixed cell population or for use in treating a senescence-related condition.
28 . Use of a compound according to any of claims 1 to 21 in the manufacture of a medicament for treating a senescence-related condition.
29 . The method, unit dose, or use of any of claims 24 to 28 , wherein the condition is osteoarthritis.
30 . The method, unit dose, or use of any of claims 24 to 28 , wherein the condition is an ophthalmic condition.
31 . The method, unit dose, or use of any of claims 24 to 28 , wherein the condition is a pulmonary disease.
32 . A method of treating cancer, comprising administering to a tissue of a subject in need thereof an amount of a compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22 effective to selectively remove cancer cells from the tissue.
33 . A compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22 for use in selectively eliminating cancer cells from a tissue or mixed cell population or for use in treating cancer.
34 . A method of treating a pulmonary disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
a compound of Formula (I):
wherein:
X 1 is —Cl;
X 2 is —COOH or —SO 2 CH 3 ;
X 3 is —SO 2 CF 3 ; —SO 2 CH 3 ; or —NO 2 ;
X 5 is —F or —H;
R 1 is —CH(CH 3 ) 2 ;
R 2 is —CH 3 ;
R 3 and R 4 are both —H;
n is 2; and
R 6 is selected from —OR 7 ,
and
R 7 is —H or —PO(OH) 2 ,
or a salt or a stereoisomer thereof; and
a pharmaceutically compatible excipient.
35 . The method of claim 34 , wherein X 2 is —COOH.
36 . The method of claim 34 , wherein X 2 is —SO 2 CH 3 .
37 . The method of claim 34 , wherein X 3 is —SO 2 CF 3 .
38 . The method of claim 34 , wherein X 3 is —SO 2 CH 3 .
39 . The method of claim 34 , wherein X 3 is —NO 2 .
40 . The method of any of claims 34 to 39 , wherein X 5 is —F.
41 . The method of any of claims 34 to 39 , wherein X 5 is —H.
42 . The method of any of claims 34 to 39 , wherein R 6 is —OR 7 .
43 . The method of any of claims 34 to 39 , wherein R 6 is
44 . The method of any of claims 34 to 39 , wherein R 6 is
45 . The method of any of claims 34 to 44 , wherein R 7 is —H.
46 . The method of any of claims 34 to 44 , wherein R 7 is —PO(OH) 2 .
47 . The method of any of claims 34 to 46 , wherein the carboxyl group in X 2 is phosphorylated.
48 . The method of claim 34 , wherein the compound is selected from the group consisting of:
49 . The method of claim 34 , wherein the pulmonary disease is idiopathic pulmonary fibrosis (IPF).
50 . The method of claim 34 , wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD).
51 . The method of claim 48 , wherein the pulmonary disease is idiopathic pulmonary fibrosis (IPF).
52 . The method of claim 48 , wherein the pulmonary disease is chronic obstructive pulmonary disease (COPD).
53 . The method of claim 34 , wherein the administration of the pharmaceutical composition is by inhalation as an aerosol.
54 . The method of claim 48 , wherein the administration of the pharmaceutical composition is by inhalation as an aerosol.Cited by (0)
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