Bile acid recycling inhibitors for treatment of obesity and diabetes

1. A method for treating diabetes comprising administering to the distal ileum, the colon, or the rectum of a diabetic individual, a pharmaceutical composition consisting essentially of a therapeutically effective amount of: (1) an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) and (2) a DPP-IV inhibitor.

2. The method of claim 1 , wherein the method reduces food intake in the individual.

3. The method of claim 1 , wherein the method induces satiety in the individual.

4. The method of claim 1 , wherein the method reduces blood and/or plasma glucose levels in the individual.

5. The method of claim 1 , wherein the method treats a metabolic disorder in the individual.

6. The method of claim 1 , wherein the method reduces the weight of the individual.

7. The method of claim 1 , wherein the method stimulates L-cells in the distal gastrointestinal tract of the individual.

8. The method of claim 1 , wherein the method increases the concentration of bile acids and salts thereof in the vicinity of L-cells in the distal gastrointestinal tract of the individual.

9. The method of claim 1 , wherein the method enhances enteroendocrine peptide secretion in the individual.

10. The method of claim 9 , wherein the enteroendocrine peptide is GLP-1, GLP-2, PYY, oxyntomodulin, or a combination thereof.

11. The method of claim 1 , wherein the ASBTI increases the level of GLP-1 in the blood and/or plasma of the individual by from about 2 times to about 6 times the level of GLP-1 in the blood and/or plasma of the individual prior to contacting the distal ileum of the individual with the ASBTI.

12. The method of claim 1 , wherein the ASBTI reduces the level of glucose in the blood and/or plasma of the individual by at least 30% compared to the level of glucose in the blood and/or plasma of the individual prior to contacting the distal ileum of the individual with the ASBTI.

13. The method of claim 1 , wherein the ASBTI maintains reduced blood and/or plasma glucose levels in the individual for at least 24 hours compared to blood and/or plasma glucose levels in the individual prior to contacting the distal ileum of the individual with the ASBTI.

14. The method of claim 1 , wherein the ASBTI is

or a pharmceutically acceptable salt thereof.

15. The method of claim 1 , wherein the ASBTI is

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the ASBTI is

or a salt thereof.

17. The method of claim 1 , wherein the ASBTI is

or a salt thereof.

18. The method of claim 1 , wherein the ASBTI is selected from the group consisting of

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α-[N—((R)-1-carboxy-2-methylthio-ethyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α-[N—((S)-1-carboxy-2-methylpropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α-[N—((S)-1-carboxybutyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxy-2-(R)-hydroxypropyl) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8—(N—{(R)—α—[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3 ,4,5-tetrahydro-1 ,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—{(S)-1[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propy}carbamoyl]benzyl}carbamoylmethoxy)-2,3 ,4,5-tetrahydro-1 ,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8[4N—{(R)-α-carboxy4-hydroxybenzyl}carbaamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the ASBTI is 1,1-dioxo-3,3-dibutyl -5-phenyl-7-methylthio-8-(N—{(R)—α—[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the ASBTI is selected from the group consisting of

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl) carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)carbamoylThenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)—α—[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , wherein the ASBTI is

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the ASBTI is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl) carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine or a pharmaceutically acceptable salt thereof.

23. A method for treating diabetes comprising administering to the distal ileum, the colon, or the rectum of a diabetic individual, a pharmaceutical composition consisting essentially of a therapeutically effective amount of: (1) a non-systemically absorbed Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) and (2) a DPP-IV inhibitor.