LPA2 receptor agonist inhibitors of CFTR
Methods and compositions for treating or preventing diarrhea are disclosed. The methods comprise administering to an individual a therapeutically effective amount of an LPA 2 receptor agonist for treating or preventing diarrhea. Also disclosed is a method of inhibiting CFTR activation by administering at least one LPA 2 receptor agonist in an amount effective to inhibit formation of a macromolecular complex between the LPA 2 receptor, CFTR, and a Na + /H + exchange regulatory factor-2 (NHERF-2).
1 . A method of treating or preventing diarrhea comprising administering to an individual a therapeutically effective amount of a composition comprising LPA, one or more LPA 2 receptor agonists, or a combination thereof.
2 . The method according to claim 1 wherein the one or more LPA 2 receptor agonists are selected from the group consisting of phosphoric acid monodecyl ester, phosphoric acid monododecyl ester, phosphoric acid monodec-9-enyl ester, phosphoric acid monododec-9-enyl ester, phosphoric acid monotetradec-9-enyl ester, phosphoric acid monotetradec-11-enyl ester, thiophosphoric acid O-decyl ester, thiophosphoric acid O-dodecyl ester, thiophosphoric acid O-tetradecyl ester, thiophosphoric acid O-dodec-9-enyl ester, thiophosphoric acid O-tetradec-9-enyl ester, thiophosphoric acid O-octadec-9-enyl ester, (R)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (S)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (R)-thiophosphoric acid O-(2,3-bis-octyloxy-propyl) ester, mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, mono potassium phosphoric acid O-(2-heptadec-9,12,15-trienyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium phosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, and combinations thereof.
3 . The method of claim 1 wherein the composition further comprises an aqueous carrier.
4 . The method of claim 3 wherein the carrier includes one or more electrolytes.
5 . The method of claim 1 wherein the step of administering is performed by providing a composition for oral consumption.
6 . The method of claim 1 wherein the step of administering is performed by providing a composition for intravenous administration.
7 . The method of claim 1 wherein the step of administering is performed prior to onset of diarrhea symptoms.
8 . The method of claim 1 wherein the step of administering is performed after onset of diarrhea symptoms.
9 . The method of claim 1 wherein the diarrhea is induced by a bacterial infection.
10 . The method of claim 9 wherein the bacterial infection is caused by Vibrio cholerae, Escherichia coli , or Clostridium difficile.
11 . The method of claim 1 wherein the diarrhea is induced by an immunoinflammatory response.
12 . A method of inhibiting cellular CFTR activity, the method comprising: contacting a cell with a composition comprising an effective amount of LPA, one or more LPA 2 receptor agonists, or a combination thereof.
13 . The method of claim 1 wherein the composition comprises a food or nutritional supplement containing an effective amount of LPA.
14 . The method according to claim 12 wherein the compound is selected from the group of phosphoric acid monodecyl ester, phosphoric acid monododecyl ester, phosphoric acid monodec-9-enyl ester, phosphoric acid monododec-9-enyl ester, phosphoric acid monotetradec-9-enyl ester, phosphoric acid monotetradec-11-enyl ester, thiophosphoric acid O-decyl ester, thiophosphoric acid O-dodecyl ester, thiophosphoric acid O-tetradecyl ester, thiophosphoric acid O-dodec-9-enyl ester, thiophosphoric acid O-tetradec-9-enyl ester, thiophosphoric acid O-octadec-9-enyl ester, (R)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (S)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (R)-thiophosphoric acid O-(2,3-bis-octyloxy-propyl) ester, mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, mono potassium phosphoric acid O-(2-heptadec-9,12,15-trienyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(l,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium phosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, and combinations thereof.
15 . A composition comprising:
an aqueous carrier,
one or more LPA 2 receptor agonists; and
one or more electrolytes.
16 . The composition of claim 15 wherein the one or more LPA 2 receptor agonists are selected from the group of phosphoric acid monodecyl ester, phosphoric acid monododecyl ester, phosphoric acid monodec-9-enyl ester, phosphoric acid monododec-9-enyl ester, phosphoric acid monotetradec-9-enyl ester, phosphoric acid monotetradec-11-enyl ester, thiophosphoric acid O-decyl ester, thiophosphoric acid O-dodecyl ester, thiophosphoric acid O-tetradecyl ester, thiophosphoric acid O-dodec-9-enyl ester, thiophosphoric acid O-tetradec-9-enyl ester, thiophosphoric acid O-octadec-9-enyl ester, (R)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (S)-octanoic acid 1-octanoyloxymethyl-2-thiophosphonooxy-ethyl ester, (R)-thiophosphoric acid O-(2,3-bis-octyloxy-propyl) ester, mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, mono potassium phosphoric acid O-(2-heptadec-9,12,15-trienyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4S) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2R,4R) mono potassium phosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, (2S,4R) mono potassium thiophosphoric acid O-(2-heptadec-9-enyl-(1,3)-dioxolan-4-ylmethyl) ester, and combinations thereof.
17 . The composition of claim 15 wherein the aqueous carrier and one or more electrolytes comprise a saline solution.
18 . The composition of claim 15 wherein the aqueous carrier and one or more electrolytes comprise Ringer's lactate.
19 . The composition of claim 15 further comprising at least one antibiotic.