Phenylsulfoxyoxazole compound inhibitors of urea transporters
View Patent ↗Provided herein are small molecule compounds that alter the transport activity of solute transporters, particularly urea transporters. The compounds described herein belong to the phenylsulfoxyoxazole, phenylsulfoxyimidazole, phenylsulfoxythiazole class of compounds. The compounds described herein are useful for increasing solute clearance in states of fluid overload and for treating cardiovascular, renal, and metabolic diseases, disorders, and conditions. Methods for identifying and using these agents that inhibit urea transporters are described herein.
1. A composition comprising a physiologically acceptable excipient and a compound having the following structure (I):
or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,
wherein
X is NR 8 , O, or S;
R 1 is —S(CH 2 ) n C(═O)NHR 10 wherein n is 1 to 6 and R 10 is hydrogen, straight-chain C 1-6 alkyl, arylalkyl, or heterocycloalkyl;
R 2 is hydrogen, hydroxyl, halogen, alkyl, aryl, arylalkyl, arylalkylamino, heterocycle or heterocycloalkyl;
R 3 , R 4 , R 5 , R 6 and R 7 are each the same or different and independently hydrogen, halogen or alkyl; and
R 8 is hydrogen or alkyl.
2. The composition of claim 1 wherein at least two of R 4 , R 5 , R 6 and R 7 are hydrogen.
3. The composition of claim 1 wherein X is O or NH.
4. The composition of claim 1 wherein R 2 is aryl, alkoxyaryl, or 5-7-membered heterocycle having at least O or S.
5. The composition of claim 1 wherein R 2 is unsubstituted phenyl or phenyl substituted with halogen, C 1-6 alkyl, or C 1-6 alkoxy at a position meta or para to the linking carbon.
6. The composition of claim 1 wherein R 2 is unsubstituted phenyl; mono-substituted phenyl with fluoro, chloro, methyl, or methoxy at a position meta or para to the linking carbon; thiophene-2-yl; or furan-2-yl.
7. The composition of claim 1 wherein each of R 4 , R 5 , R 6 and R 7 is the same or different and independently hydrogen, or halogen, or C 1-6 alkyl.
8. The composition of claim 1 wherein each of R 4 , R 5 , R 6 and R 7 is hydrogen.
9. The composition of claim 1 wherein R 3 is hydrogen, halogen, or C 1-6 alkyl.
10. The composition of claim 1 wherein R 3 is hydrogen, halogen, or methyl.
11. The composition of claim 1 wherein X is O.
12. The composition of claim 1 wherein R 1 is
—S-(2-mercaptoacetamidyl);
—S—[N-(furan-2-yl-methyl)-2-mercaptoacetamidyl);
—S-mercaptomethyl;
sulfhydryl; or
—S-benzothioate.
13. The composition of claim 11 wherein R 1 is —S-(2-mercaptoacetamidyl) and the compound has the following substructure (Ia):
or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof.
14. The composition of claim 13 wherein R 2 is unsubstituted aryl, mono-substituted aryl wherein the substituent is meta or para to the linking carbon, or substituted or unsubstituted heterocycle.
15. The composition of claim 13 wherein R 2 is unsubstituted phenyl; mono-substituted phenyl wherein the substituent is meta or para to the linking carbon and is halogen, C 1-6 alkyl, or C 1-6 alkoxy; or a five- or six-member heteroaryl having at least O or S.
16. The composition of claim 13 wherein R 2 is unsubstituted phenyl; mono-substituted phenyl with fluoro, chloro, or methyl, at a position meta or para to the linking carbon; thiophene-2-yl; or furan-2-yl.
17. The composition of claim 13 wherein each of R 4 , R 5 , R 6 and R 7 is the same or different and independently hydrogen, or halogen, or C 1-6 alkyl.
18. The composition of claim 13 wherein each of R 4 , R 5 , R 6 and R 7 is hydrogen.
19. The composition of claim 13 wherein R 3 is hydrogen, halogen, or C 1-6 alkyl.
20. The composition of claim 13 wherein R 3 is hydrogen, halogen, or methyl.
21. The composition of claim 13 wherein the compound is
2-(4-(4-bromophenylsulfonyl)-2-phenyloxazol-5-ylthio)acetamide,
2-(4-(4-chlorophenylsulfonyl)-2-phenyloxazol-5-ylthio)acetamide,
2-(2-phenyl-4-tosyloxazol-5-ylthio)acetamide,
2-(2-phenyl-4-(phenylsulfonyl)oxazol-5-ylthio)acetamide,
2-(2-(4-fluorophenyl)-4-tosyloxazol-5-ylthio)acetamide,
2-(4-(4-chlorophenylsulfonyl)-2-(4-fluorophenyl)oxazol-5-ylthio)acetamide,
2-(2-(4-fluorophenyl)-4-(4-fluorophenylsulfonyl)oxazol-5-ylthio)acetamide,
2-(2-(4-fluorophenyl)-4-(phenylsulfonyl)oxazol-5-ylthio)acetamide,
2-(4-(4-bromophenylsulfonyl)-2-p-tolyloxazol-5-ylthio)acetamide,
2-(2-p-tolyl-4-tosyloxazol-5-ylthio)acetamide,
2-(4-(4-chlorophenylsulfonyl)-2-p-tolyloxazol-5-ylthio)acetamide,
2-(4-(phenylsulfonyl)-2-p-tolyloxazol-5-ylthio)acetamide,
2-(4-(4-chlorophenylsulfonyl)-2-(thiophen-2-yl)oxazol-5-ylthio)acetamide,
2-(2-(thiophen-2-yl)-4-tosyloxazol-5-ylthio)acetamide,
2-(4-(4-fluorophenylsulfonyl)-2-(thiophen-2-yl)oxazol-5-ylthio)acetamide,
2-(4-(phenylsulfonyl)-2-(thiophen-2-yl)oxazol-5-ylthio)acetamide,
2-(4-(4-chlorophenylsulfonyl)-2-(furan-2-yl)oxazol-5-ylthio)acetamide,
2-(4-(4-bromophenylsulfonyl)-2-(furan-2-yl)oxazol-5-ylthio)acetamide, or
2-(2-(furan-2-yl)-4-tosyloxazol-5-ylthio)acetamide.
22. The composition of claim 11 wherein R 1 is S—N-(furan-2-yl-methyl)-2-mercaptoacetamidyl) and each of R 4 , R 5 , R 6 and R 7 is hydrogen and the compound has the following substructure of formula (Ic):
or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein R 3 is hydrogen, halogen, or alkyl.
23. The composition of claim 11 wherein R 3 is hydrogen, halogen, or methyl.
24. The composition of claim 11 wherein R 3 is bromo or chloro.
25. The composition of claim 22 wherein R 2 is unsubstituted aryl; mono-substituted aryl wherein the substituent is meta or para to the linking carbon; or substituted or unsubstituted heterocycle.
26. The composition of claim 22 wherein R 2 is unsubstituted phenyl; or mono-substituted phenyl wherein the substituent is meta or para to the linking carbon and the substituent is halogen, C 1-6 alkyl, or C 1-6 alkoxy.
27. The composition of claim 22 wherein R 2 is unsubstituted phenyl.
28. The compound of claim 22 wherein the compound is 2-(4-(4-bromophenylsulfonyl)-2-phenyloxazol-5-ylthio)-N-(furan-2-ylmethyl)acetamide or 2-(4-(4-chlorophenylsulfonyl)-2-phenyloxazol-5-ylthio)-N-(furan-2-ylmethyl)acetamide.
29. The composition of claim 1 wherein R 2 is phenyl, 2-fluorophen-2-yl, 4-fluorophen-1-yl, 2-chlorophen-1-yl, 4-methylphen-1-yl, 2-methyoxyphen-1-yl, thiophene-2-yl, or furan-2-yl.
30. The composition of claim 1 wherein R 3 is hydrogen, fluoro, chloro, bromo or methyl.
31. The composition of claim 1 wherein X is NH.
32. A method for treating a disease or disorder associated with aberrant transport of urea in a subject by administering to the subject the composition according to claim 1 .
33. The method of claim 32 wherein the disease or disorder is associated with a fluid retention imbalance.
34. The method according to claim 33 wherein the fluid retention imbalance comprises urea clearance insufficiency.
35. The method according to claim 34 wherein urea clearance insufficiency is renal urea clearance insufficiency.
36. The method of claim 32 wherein the disease or disorder is selected from a cardiovascular disease, syndrome of inappropriate antidiuretic hormone secretion (SIADH), cirrhosis, azotemia, acute renal failure, chronic renal insufficiency, fluid retention, and abnormal uresis.
37. The method of claim 36 wherein the cardiovascular disease or disorder is hypertension or congestive heart failure.
38. The method according to claim 32 wherein treating the disease or disorder comprises inhibiting transport of urea by at least one urea transporter.
39. The method according to claim 38 wherein the at least one urea transporter is a UT-B transporter.
40. The method according to claim 38 wherein the at least one urea transporter is a UT-A transporter selected from UT-A1, UT-A2, UT-A3, UT-A4, and UT-A5.