EPITHELIAL SODIUM CHANNEL (ENAC) INHIBITOR CONJUGATES AND METHODS FOR USE THEREOF
This disclosure relates to epithelial sodium channel (ENaC) inhibitory conjugates, compositions thereof, and method of use thereof. In particular the ENaC inhibitory conjugates of the present disclosure comprise peptides linked to Amiloride, and are useful for treating pulmonary diseases or disorder, including cystic fibrosis, chronic obstructive pulmonary disease, asthma, emphysema, primary ciliary dyskinesia, or pneumonia.
1 . A conjugate of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
L is a bond,
R is H or phenyl; and
A is a peptide designed to be retained in the lungs or a derivative thereof.
2 . The conjugate of claim 1 , wherein the peptide comprises ASHLRKLRKRL (SEQ ID NO: 1) or a derivative thereof.
3 . The conjugate of claim 2 , wherein the peptide derivative is acetylated, lipidated, amidated, derivatized with D-alanine, or derivatized with alpha-aminoisobutyric acid.
4 . The conjugate of claim 1 , wherein the peptide comprises SHLRKLRKRLL (SEQ ID NO: 58).
5 . The conjugate of claim 1 , wherein the peptide comprises ASHLRKLRKRLL (SEQ ID NO: 59).
6 . The conjugate of claim 2 , wherein the peptide comprises an additional leucine on the C-terminus of SEQ ID NO: 1.
7 . The conjugate of claim 1 , wherein the peptide is any one of SEQ ID NOs: 2-13 and 56-57.
8 . The conjugate of any one of claims 1-7 , wherein the peptide is bound to L at the C-terminus.
9 . The conjugate of any one of claims 1-7 , wherein the peptide is bound to L at the N-terminus.
10 . The conjugate of any one of claims 1-7 , wherein the peptide is bound to L at an amino acid side chain residue of the peptide.
11 . The conjugate of claim 1 , selected from any one of SEQ ID NOs: 14-55.
12 . A pharmaceutical composition comprising any one of the conjugate of claims 1-11 and a pharmaceutically acceptable carrier or excipient.
13 . A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 1-11 or a pharmaceutical composition of claim 12 .
14 . The method of claim 13 , wherein the disease or disorder is a pulmonary disease or disorder.
15 . The method of claim 13 , wherein the pulmonary disease or disorder is cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, emphysema, primary ciliary dyskinesia, pneumonia, or non-cystic fibrosis bronchiectasis.
16 . The method of any one of claims 13-15 , wherein the subject is a mammal.
17 . The method of any one of claims 13-16 , wherein the subject is a human.
18 . The method of any one of claims 13-17 , wherein the conjugate or the pharmaceutical composition is administered once a day.
19 . The method of any one of claims 13-18 , wherein the conjugate or the pharmaceutical composition is administered multiple times a day.
20 . The method of any one of claims 13-19 , wherein the conjugate is administered at a dose ranging from about 0.1 mg/kg to about 100 mg/kg.
21 . The method of any one of claims 13-20 , wherein the conjugate or the pharmaceutical composition is administered intranasally, intratracheally, intrapulmonary, intrabronchially, or by inhalation.