Modulation of chemosensory receptors and ligands associated therewith

• US 9,603,848 B2
• Filed: 06/08/2007
• Issued: 03/28/2017
• Est. Priority Date: 06/08/2007
• Status: Active Grant

• Current Assignee: Firmenich Inc (DSM-Firmenich AG)
• Original Assignee: Senomyx Inc (DSM-Firmenich AG)
• Inventors: Servant, Guy, Li, Xiaodong, Zhang, Feng, Liu, Haitian, Tachdjian, Catherine, Tang, Xiao-Qing, Werner, Sara, Rinnova, Marketa, Chen, Qing, Zlotnik, Albert, Zoller, Mark, Klebansky, Boris, Fine, Richard, Kang, Xinshan
• Primary Examiner(s): Klinkel, Kortney L
• Assistant Examiner(s): LEE, WILLIAM Y
• Application Number:
  US11/760,592
• Publication Number:
  US 20080306093A1
• Time in Patent Office: 3,581 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 285/15 Six-membered rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: G16B 15/00 ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 15/20 Protein or domain folding
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 Mutagenesis

Abstract

The present invention provides screening methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors as well as modifiers capable of modulating chemosensory receptors and their ligands.

Claims

1. A method of modulating the sweet taste of a composition comprising contacting a composition with a compound having structural Formula (III):

2. The method of claim 1, wherein the modified composition comprises at least about 0.001 ppm of the compound.

3. The method of claim 1, wherein the modified composition comprises about 0.001 ppm to about 100,000 ppm of the compound.

4. The method of claim 1, wherein the modified composition comprises about 0.0001 ppm to about 10 ppm of the compound.

5. The method of claim 1, wherein the modified composition comprises about 0.01 ppm to about 100 ppm of the compound.

6. The method of claim 1, wherein the compound having structure Formula (III) is selected from the group consisting of:

7. The method of claim 1, wherein the composition is a comestible or medicinal product.

8. The method of claim 7, wherein the comestible product is a food or beverage product.

9. The method of claim 1, wherein the modified composition comprises at least a sweet flavor entity.

10. The method of claim 9, wherein the sweet flavor entity is selected from the group consisting of cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, aspartame, neotame and other aspartame derivatives, saccharin, sucralose, acesulfame K, glucose, erythritol, D-tryptophan, glycine, mannitol, sorbitol, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), stevioside, rebaudioside A, alitame, carrelame, tagatose, xylitol, high fructose corn syrup, and combinations thereof.

11. The method of claim 10, wherein the sweet flavor entity is sucralose, sucrose, or fructose.

12. The method of claim 1, wherein R³⁸ is hydrogen or —

OR⁴⁵.

13. The method of claim 12, wherein R⁴⁵ is —

C₁-C₆ alkyl-C₃-C₁₀ cycloalkyl, —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl, or —

C₂-C₆ alkenyl-O—

C₁-C₆ alkyl.

14. The method of claim 12, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

15. The method of claim 12, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, or —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl.

16. The method of claim 12, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

17. The method of claim 1, wherein R³⁸ is hydrogen or —

NR⁴⁵R⁴⁶;

R⁴⁵ is —

C₁-C₆ alkyl; and

R⁴⁶ is hydrogen.

18. The method of claim 17, wherein R⁴⁵ is —

C₁-C₃ alkyl.

19. A compound having structural Formula (III):

20. The compound of claim 19, wherein R⁴⁵ is C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

21. The compound of claim 20, wherein R⁴⁵—

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, or —

C₁-C₆ alkyl-NHC(O)-heteroaryl.

22. The compound of claim 20, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, or —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl.

23. The compound of claim 20, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, or —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl.

24. The compound of claim 20, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-heteroaryl.

25. A method of preparing a final beverage product comprising contacting a first beverage product with a solid or liquid concentrate composition comprising a compound having structural Formula (III) or a salt or solvate thereof,

26. The method of claim 25, wherein the final beverage product comprises at least about 0.001 ppm of the compound.

27. The method of claim 25, wherein the final beverage product comprises about 0.001 ppm to about 100,000 ppm of the compound.

28. The method of claim 25, wherein the final beverage product comprises about 0.0001 ppm to about 10 ppm of the compound.

29. The method of claim 25, wherein the final beverage product comprises about 0.01 ppm to about 100 ppm of the compound.

30. The method of claim 25, wherein the final beverage product comprises at least a sweet flavor entity.

31. The method of claim 30, wherein the sweet flavor entity is selected from the group consisting of cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, aspartame, neotame and other aspartame derivatives, saccharin, sucralose, acesulfame K, glucose, erythritol, D-tryptophan, glycine, mannitol, sorbitol, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), stevioside, rebaudioside A, alitame, carrelame, tagatose, xylitol, high fructose corn syrup, and combinations thereof.

32. The method of claim 31, wherein the sweet flavor entity is sucralose, sucrose, or fructose.

33. The method of claim 25, wherein the compound having structure Formula (III) is selected from the group consisting of:

34. The method of claim 25, wherein R³⁸ is hydrogen or —

OR⁴⁵.

35. The method of claim 34, wherein R⁴⁵ is —

C₁-C₆ alkyl-C₃-C₁₀ cycloalkyl, —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl, or —

C₂-C₆ alkenyl-O—

C₁-C₆ alkyl.

36. The method of claim 34, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

37. The method of claim 34, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, or —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl.

38. The method of claim 34, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

39. The method of claim 25, wherein R³⁸ is hydrogen or —

NR⁴⁵R⁴⁶;

R⁴⁵ is —

C₁-C₆ alkyl; and

R⁴⁶ is hydrogen.

40. The method of claim 39, wherein R⁴⁵ is —

C₁-C₃ alkyl.

41. A method of supplying a flavor preparation comprising providing to an entity a solid or liquid concentrate composition comprising a compound of Formula (III):

42. The method of claim 41, wherein R³⁸ is hydrogen or —

OR⁴⁵.

43. The method of claim 42, wherein R⁴⁵ is —

C₁-C₆ alkyl-C₃-C₁₀ cycloalkyl, —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl, or —

C₂-C₆ alkenyl-O—

C₁-C₆ alkyl.

44. The method of claim 42, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl, —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

45. The method of claim 42, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-aryl, —

C₁-C₆ alkyl-NHC(O)—

C₁-C₆ alkyl, or —

C₁-C₆ alkyl-C(O)NH—

C₁-C₆ alkyl.

46. The method of claim 42, wherein R⁴⁵ is —

C₁-C₆ alkyl-NHC(O)-heteroaryl, or —

C₁-C₆ alkyl-cycloheteroalkyl-C(O)—

C₁-C₆ alkyl.

47. The method of claim 41, wherein R³⁸ is hydrogen or —

NR⁴⁵R⁴⁶;

R⁴⁵ is —

C₁-C₆ alkyl; and

R⁴⁶ is hydrogen.

48. The method of claim 47, wherein R⁴⁵ is —

C₁-C₃ alkyl.