Remodilins for airway remodeling and organ fibrosis
AssigneesThe University of Chicago, The United States of America, as represented by the Secretary, Department of Health and Human Servic, President and Fellows of Harvard College, IIT Research Institute, Beth Israel Deaconess Medical Center, Inc.
InventorsJulian SOLWAY, Nickolai DULIN, Diane Luci, David MALONEY, Chan Young PARK, Jeffrey FREDBERG, David MCCORMICK, Ramaswamy KRISHNAN
Life of this patent
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Abstract
Disclosed herein is a class of molecules termed remodilins that are effective in treating asthma, pulmonary fibrosis, and associated disorders. The molecules ameliorate asthma and pulmonary fibrosis symptoms by various mechanisms, including inhibiting airway smooth muscle contractile protein accumulation, reducing airway constrictor hyperresponsiveness, inhibiting bronchial fibroblast transformation into myofibroblasts, and/or treating or preventing airway or pulmonary fibrosis.
Claims87
A composition comprising a compound of Formula 1:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle.
A composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a salt, enantiomer, or diastereomer thereof.
A method of treating fibrosis comprising administering to a subject a composition comprising a compound of Formula I:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of preventing or inhibiting contractile protein accumulation in a subject comprising administering to the subject a composition comprising a compound of Formula I:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of preventing or inhibiting the transformation of fibroblast into myofibroblasts in a subject comprising administering to the subject a composition comprising a compound of Formula I:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of treating or preventing airway constrictor hyperresponsiveness in a subject comprising administering to the subject a composition comprising a compound of Formula I:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of treating a disease of the airway in a subject comprising administering to the subject a composition comprising a compound of Formula I:
- where:
- A is —CH— or —N—;
- B is —C(O)—NH—, —NH—C(O)—, —CH2—NH—, or —C(NH)—NH—;
- X is —(Y)—NR3R4 or NHSO2Me;
- Y is —SO2—, —C(O)—, or —(CH2)—;
- R1 and R2 are each independently hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, alkoxy, halide, nitrile, amine, acylamine, substituted or unsubstituted aryl, 4-6 member carbocycle, substituted or unsubstituted heterocycle, and
- R3 and R4 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle, substituted or unsubstituted bicyclic, or may join to form a carbocycle or heterocycle;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of treating fibrosis comprising administering to a subject a composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of preventing or inhibiting contractile protein accumulation in a subject comprising administering to the subject a composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of preventing or inhibiting the transformation of fibroblasts into myofibroblasts in a subject comprising administering to the subject a composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of treating or preventing airway constrictor hyperresponsiveness in a subject comprising administering to the subject a composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
A method of treating a disease of the airway in a subject comprising administering to the subject a composition comprising a compound of Formula II:
- where:
- R5 and R6 are each independently hydrogen, halide, substituted or unsubstituted alkyl, alkoxy, amine, alkylamine, sulfonamide, or join together to form a 5 or 6 member carbocycle or heterocycle;
- and
- R7 and R8 are each independently hydrogen, alkyl, or substituted or unsubstituted aryl, wherein the substituted aryl may be substituted with amide, sulfonamide, substituted or unsubstituted alkyl, or two adjacent carbon atoms on the substituted aryl ring form a carbocycle or heterocycle ring;
- or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof.
Dependencies are inferred from the claim text.