Small molecule inhibitors of ghrelin O-acyltransferase

1. A pharmaceutical composition comprising a ghrelin O-acyltransferase (GOAT) inhibitor of structure 1:

wherein:

R 1 is selected from n-heptanyl, n-heptenyl, n-heptynyl, and methyl-diethylene glycol (—CH 2 OCH 2 CH 2 OCH 2 CH 3 );

R 3 -R 5 are independently selected from an electron pair, hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, and an optionally substituted heteroatom;

A is selected from CH 2 , O, S, NH, and N-alkyl;

G is selected from O, S, NH, and N-alkyl;

X is selected from hydroxyl, amino, alkylamino, and alkylthio;

Y is C; and

Z is selected from CH 2 , O, S, NH and N-alkyl,

or a pharmaceutically acceptable salt thereof, wherein said inhibitor inhibits said ghrelin O-acyltransferase (GOAT), and said composition is suitable for pharmaceutical use,

wherein R 2 is optionally-substituted, lower (C1-C5) alkyl.

2. The composition of claim 1 wherein R 1 is n-heptanyl.

3. The composition of claim 1 wherein R 2 is methyl, ethyl, propyl or butyl.

4. The composition of claim 1 wherein R 3 is H or optionally substituted, lower (C1-C5) alkyl.

5. The composition of claim 1 wherein R 3 is H, methyl, ethyl, propyl or butyl.

6. The composition of claim 1 wherein R 4 is methoxy.

7. The composition of claim 1 wherein R 4 is of structure 2:

wherein:

R 7 is the point of attachment and is selected from a bond, optionally substituted lower alkyl, NH, S and O;

R 8 and R 9 are independently selected from hydrogen and optionally hetero-, optionally substituted alkyl; and

D is selected from C, N, and R 10 is a 5-7 membered, optionally heterocyclic ring.

8. The composition of claim 1 wherein R 5 is R 6 (CH 2 ) n wherein R 6 is a 5-7 membered, optionally heterocyclic ring, and n is an integer from 0 to 5.

9. A pharmaceutical composition comprising a ghrelin O-acyltransferase (GOAT) inhibitor of structure 1:

wherein:

R 1 is selected from n-heptanyl, n-heptenyl, n-heptynyl, and methyl-diethylene glycol (—CH 2 OCH 2 CH 2 OCH 2 CH 3 );

R 2 , R 3 and R 5 are independently selected from an electron pair, hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, and an optionally substituted heteroatom;

A is selected from CH 2 , O, S, NH, and N-alkyl;

G is selected from O, S, NH, and N-alkyl;

X is selected from hydroxyl, amino, alkylamino, and alkylthio;

Y is C; and

Z is selected from CH 2 , O, S, NH and N-alkyl,

or a pharmaceutically acceptable salt thereof, wherein said inhibitor inhibits said ghrelin O-acyltransferase (GOAT), and said composition is suitable for pharmaceutical use,

wherein R 4 is methoxy.

10. The composition of claim 9 wherein R 1 is n-heptanyl.

11. The composition of claim 9 wherein R 2 is optionally-substituted, lower (C1-C5) alkyl.

12. The composition of claim 9 wherein R 2 is methyl, ethyl, propyl or butyl.

13. The composition of claim 9 wherein R 3 is H or optionally substituted, lower (C1-C5) alkyl.

14. The composition of claim 9 wherein R 3 is H, methyl, ethyl, propyl or butyl.

15. The composition of claim 9 wherein R 5 is R 6 (CH 2 ) n wherein R 6 is a 5-7 membered, optionally heterocyclic ring, and n is an integer from 0 to 5.

16. A pharmaceutical composition comprising a ghrelin O-acyltransferase (GOAT) inhibitor of structure 1:

wherein:

R 1 is selected from n-heptanyl, n-heptenyl, n-heptynyl, and methyl-diethylene glycol (—CH 2 OCH 2 CH 2 OCH 2 CH 3 );

R 2 -R 4 are independently selected from an electron pair, hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, and an optionally substituted heteroatom;

A is selected from CH 2 , O, S, NH, and N-alkyl;

G is selected from O, S, NH, and N-alkyl;

X is selected from hydroxyl, amino, alkylamino, and alkylthio;

Y is C; and

Z is selected from CH 2 , O, S, NH and N-alkyl,

or a pharmaceutically acceptable salt thereof, wherein said inhibitor inhibits said ghrelin O-acyltransferase (GOAT), and said composition is suitable for pharmaceutical use,

wherein R 5 is R 6 (CH 2 ) n wherein R 6 is a 5-7 membered, optionally heterocyclic ring, and n is an integer from 0 to 5.

17. The composition of claim 16 wherein R 1 is n-heptanyl.

18. The composition of claim 16 wherein R 2 is optionally-substituted, lower (C1-C5) alkyl.

19. The composition of claim 16 wherein R 2 is methyl, ethyl, propyl or butyl.

20. The composition of claim 16 wherein R 3 is H or optionally substituted, lower (C1-C5) alkyl.

21. The composition of claim 16 wherein R 3 is H, methyl, ethyl, propyl or butyl.

22. The composition of claim 16 wherein R 4 is methoxy.

23. The composition of claim 16 wherein R 4 is of structure 2:

wherein:

R 7 is the point of attachment and is selected from a bond, optionally substituted lower alkyl, NH, S and O;

R 8 and R 9 are independently selected from hydrogen and optionally hetero-, optionally substituted alkyl; and

D is selected from C, N, and R 10 is a 5-7 membered, optionally heterocyclic ring.

24. A pharmaceutical composition comprising a ghrelin O-acyltransferase (GOAT) inhibitor or a pharmaceutically acceptable salt thereof, wherein said inhibitor is of a structure selected from the group consisting of:

PH1147

PH1149

PH1150

PH1154

PH1154a

PH1156

PH1159

PH1165

PH1167

BK1112

BK1129

BK1149

BK1135

BK1141

BK1145

LN1111622

PH1176a

PH1176b

25. A method of inhibiting ghrelin O-acyltransferase (GOAT), comprising the steps of contacting the GOAT with the composition of claim 9 , and detecting a resultant inhibition of the GOAT.

26. A method of inhibiting ghrelin O-acyltransferase (GOAT), comprising the steps of contacting the GOAT with the composition of claim 9 , and detecting a resultant inhibition of the GOAT.

27. A method of inhibiting ghrelin O-acyltransferase (GOAT), comprising the steps of contacting the GOAT with the composition of claim 16 , and detecting a resultant inhibition of the GOAT.

28. A method of inhibiting ghrelin O-acyltransferase (GOAT), comprising the steps of contacting the GOAT with the composition of claim 24 , and detecting a resultant inhibition of the GOAT.