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[0016]FIGS. 6A-6C. Topical CFTRact-K089 restores tear secretion and prevents corneal epithelial disruption following LGE. FIG. 6A) Basal tear secretion following extraorbital LGE in BALB/c mice, comparing eyes treated with CFTRact-K089 (mean±SEM, 15 eyes) to vehicle (n=1 eyes). Tear volume was measured immediately prior to LGE, and then one hour after the first
Problems solved by technology
Constipation is a common clinical complaint in adults and children that negatively impacts quality of life.
There are two FDA-approved chloride channel activators, lubiprostone and linaclotide, for treatment of constipation, but clinical trials showed variable and unimpressive efficacy of both drugs.
Dry eye is a heterogeneous tear film disor
Method used
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embodiment p1
[0261]A pharmaceutical composition, comprising a pharmaceutically acceptable excipient, and a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein: Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L1 and L2 are independently substituted or unsubstituted C1-C3 alkylene; n1 is an integer from 0 to 4; m1 and v1 are independently 1 or 2; R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, —CX2.13, —CHX2.12, —CH2X2.1, —CN, —SOn1R2A, —SOv1NR2BR2C,...
embodiment p2
[0262]The pharmaceutical composition of embodiment P1, wherein: Ar is unsubstituted heteroaryl; L1 and L2 are independently —CH2—; and R1, R2, R3, R4 and R5 are independently hydrogen, —OCH3 or —OCH2CH3.
embodiment p3
[0263]The pharmaceutical composition of embodiment P2, wherein R1, R4 and R5 are independently hydrogen.
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Abstract
Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders or other diseases and disorders.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 387,591, filed Dec. 24, 2015, the contents of which is incorporated herein in its entirety and for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with the government support under Grant Nos. TR000004, EY023981, EY013574, EB000415, DK035124, DK072517 and DK101373, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Constipation is a common clinical complaint in adults and children that negatively impacts quality of life. The prevalence of chronic constipation has been estimated to be 15% in the U.S. population, with health-care costs estimated at approximately 7 billion dollars annually, with in excess of 500 million dollars spent on laxatives. The mainstay of constipation therapy includes laxatives an...
Claims
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