Dual PPAR-δ PPAR-γ agonists

Patent metadata

Field	Value
Publication number	US-9422239-B1
Application number	US-201414212864-A
Country	US
Kind code	B1
Filing date	Mar 14, 2014
Priority date	Mar 14, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present disclosure provides novel compounds with activity as PPARβ/δ and PPARγ dual agonists. The disclosure also provides methods of treating diabetes mellitus and methods of treating Alzheimer's disease utilizing the novel compounds, as well as pharmaceutical formulations comprising the novel compounds.

First claim

What is claimed is:

1. A composition comprising a compound selected from the group consisting of

or pharmaceutically acceptable salt thereof.

2. The composition of claim 1 , wherein the compound is an agonist of a PPARδ receptor.

3. The composition of claim 2 , wherein the compound has a binding affinity for the PPARδ receptor between −10.0 and −12.0 kcal/mol.

4. The composition of claim 2 , wherein the compound binds with an amino acid residue of the PPARδ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Cys285, Thr288, Thr289, Leu330, Val334, Leu339, Leu353, and Phe368.

5. The composition of claim 4 , wherein the binding between the compound and the amino acid residue is a hydrogen bond.

6. The composition of claim 1 , wherein the compound is an agonist of a PPARγ receptor.

7. The composition of claim 6 , wherein the compound has a binding affinity for the PPARγ receptor between −10.0 and −12.0 kcal/mol.

8. The composition of claim 6 , wherein the compound binds with an amino acid residue of the PPARγ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Leu228, Cys285, Gln286, Arg288, Ser289, Glu295, Met329, Leu330, Ser342, Glu343, Phe363, and His 449.

9. The composition of claim 8 , wherein the binding between the compound and the amino acid residue is a hydrogen bond.

10. The composition of claim 1 , wherein the compound is an agonist of a PPARδ receptor and an agonist of a PPARγ receptor.

11. The composition of claim 1 , wherein the compound permeates the blood-brain barrier.

12. A pharmaceutical formulation comprising a therapeutically effective amount of a compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

13. The pharmaceutical formulation of claim 12 further comprising at least one additional active ingredient.

14. The pharmaceutical formulation of claim 12 , wherein the pharmaceutical formulation is an oral formulation.

15. The pharmaceutical formulation of claim 12 , wherein the compound permeates the blood-brain barrier.

16. The composition of claim 1 , wherein the compound is

17. The composition of claim 1 , wherein the compound is

18. The composition of claim 1 , wherein the compound is

19. The composition of claim 1 , wherein the compound is

Assignees

• Amin Rajesh
• Boncher Tracey
• Acevedo Orlando
• Univ Auburn
• Ferris State Univ

Inventors

• Amin Rajesh
• Boncher Tracey
• Acevedo Orlando

Classifications

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• C07C229/38

  having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton · CPC title

• A61K31/195

  having an amino group · CPC title

• C07D209/48 Primary

  with oxygen atoms in positions 1 and 3, e.g. phthalimide · CPC title