Treatments for female sexual dysfunction and methods for identifying compounds useful for treating female sexual dysfunction

• US 20030083228A1
• Filed: 08/20/2002
• Published: 05/01/2003
• Est. Priority Date: 08/21/2001
• Status: Abandoned Application

• Current Assignee: John R. Hadcock, Philip A. Carpino
• Original Assignee: John R. Hadcock, Philip A. Carpino
• Inventors: Hadcock, John R., Carpino, Philip A.
• Application Number:
  US10/225,258
• Publication Number:
  US 20030083228A1
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides a method of treating female sexual dysfunction, the method comprising the step of administering to a patent, having or at risk of having one or more of the disorders or conditions associated with female sexual dysfunction, a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α-melanocyte stimulating hormone to melanocortin receptors. The present invention also provides a method of identifying a compound that is useful for the treatment or prevention of female sexual dysfunction, the method comprising the steps of: 1) determining if a compound affects the binding of agouti-related protein to melanocortin receptors; 2) determining if a compound affects the binding of α-melanocyte stimulating hormone to melanocortin receptors; and 3) selecting a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not affect the binding of α-melanocyte stimulating hormone to melanocortin receptors.

Claims

1. A method of treating female sexual dysfunction which comprises administering to a female patient in need thereof a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

2. A method of claim 1 wherein the female sexual dysfunction is other than hypoactive sexual desire disorder, sexual anhedonia or dyspareunia.

7. A method of claim 1 wherein the melanocortin receptors are melanocortin-4 or melanocortin-3 receptors.

8. A method of claim 1 wherein the melanocortin receptors are melanocortin-4 receptors.

9. A method of claim 1 wherein the female patient is a post-menopausal woman.

10. A method of claim 1 which further comprises co-administering a therapeutically effective amount of a melanocortin receptor agonist.

11. A method of claim 1 which further comprises co-administering a therapeutically effective amount of an estrogen agonist/antagonist of a pharmaceutically acceptable salt thereof.

12. A method of claim 11 wherein the estrogen agonist/antagonist is of the following formula (I):

13. A method of claim 12 wherein said estrogen agonist/antagonist is a compound of formula (IA):

14. A method of claim 13 wherein said estrogen agonist/antagonist is (−

)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof;

a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.

15. A method of claim 14 wherein said estrogen agonist/antagonist is in the form of a D-tartrate salt.

16. A method of claim 11 wherein said estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof;

and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.

17. A method of claim 11 wherein said estrogen agonist/antagonist is a compound selected from the formulas V or VI:

18. A method of claim 17 wherein said estrogen agonist/antagonist is the compound, TSE-424, of formula Va below:

19. A method of claim 11 wherein said estrogen agonist/antagonist is EM-652 of formula III below or is EM-800 of formula IV below:

20. A method of claim 1 which further comprise co-administering a therapeutically effective amount of a cyclic guanosine 3′

,5′

-monophosphate elevator.

21. A method of claim 20 wherein said cyclic guanosine 3′

,5′

-monophosphate elevator is a PDE_V phosphodiesterase inhibitor.

22. A method of claim 21 wherein the PDE_V phosphodiesterase inhibitor is 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sufonyl]-4-methylpiperazine citrate salt.

23. A method of claim 1 which further comprise co-administering a therapeutically effective amount of an estrogen.

24. A method of claim 1 which further comprise co-administering a therapeutically effective amount of an estrogen and a progestin.

25. A method of claim 23 wherein the estrogen is Premarin®

.

26. A method of claim 1 which further comprises co-administering a therapeutically effective amount of a compound selected from the group consisting of:

Prostaglandins;

Apomorphine;

Oxytocin modulators;

α

-2 Adrenergic antagonists;

Androgens;

selective androgen receptor modulators (SARMs);

bupropion;

Vasoactive intestinal peptide (VIP);

Neutral endopeptidase inhibitors (NEP); and

Neuropeptide Y receptor antagonists (NPY).

3. A method of treating sexual arousal disorder in a female patient which comprises administering to a female patient in need thereof a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

4. A method of treating vaginismus in a female patient which comprises administering to a female patient in need thereof a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

5. A method of increasing the frequency or intensity of orgasms in a female patient which comprises administering to a female patient in need thereof a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

6. A method of enhancing libido more than normal in a female patient which comprises administering to a female patient in need thereof a therapeutically effective amount of a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

27. A method of identifying a compound that is useful for the treatment of female sexual dysfunction which comprises the steps of:

1) determining if a compound affects the binding of agouti-related protein to melanocortin receptors;

2) determining if a compound affects the binding of α

-melanocyte stimulating hormone to melanocortin receptors; and

3) selecting a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

28. The method of claim 27 wherein the determination of whether a compound affects the binding of agouti-related protein to melanocortin receptors is accomplished using a competitive binding assay.

29. The method of claim 27 wherein the determination of whether a compound affects the binding of α

-melanocyte stimulating hormone to melanocortin receptors is accomplished using a competitive binding assay.

30. The method of claim 27 wherein the determination of whether a compound affects the binding of agouti-related protein to melanocortin receptors is accomplished using a competitive binding assay and the determination of whether a compound affects the binding of α

-melanocyte stimulating hormone to melanocortin receptors is accomplished using a competitive binding assay.

31. The method of claim 27 wherein the melanocortin receptors are melanocortin-3 or melanocortin-4 receptors.

32. The method of claim 27 wherein the melanocortin receptors are melanocortin-4 receptors.

33. A pharmaceutical composition for treating female sexual dysfunction which comprises a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors.

34. A pharmaceutical composition for treating female sexual dysfunction which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors; and

     2) a compound that is a melanocortin receptor agonist.

35. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, and

     2) an estrogen agonist/antagonist or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition of claim 35 wherein said estrogen agonist/antagonist is of the following formula (I):

38. A composition of claim 37 wherein said estrogen agonist/antagonist is a compound of formula (IA):

39. A composition of claim 38 wherein said estrogen agonist/antagonist is (−

)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof;

a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.

40. A composition of claim 39 wherein said estrogen agonist/antagonist is in the form of a D-tartrate salt.

41. A composition of claim 35 wherein said estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof;

and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.

42. A composition of claim 35 wherein said estrogen agonist/antagonist is a compound selected from the formulas V or VI:

43. A composition of claim 42 wherein said estrogen agonist/antagonist is the compound, TSE-424, of formula Va below:

44. A composition of claim 35 wherein said estrogen agonist/antagonist is EM-652 of formula III below or is EM-800 of formula IV below:

60. A composition of claim 35 wherein the melanocortin receptors are melanocortin-4 or melanocortin-3 receptors.

61. A composition of claim 35 wherein the melanocortin receptors are melanocortin-4 receptors.

36. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors;

     2) a compound that is a melanocortin receptor agonist; and

     3) an estrogen agonist/antagonist or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition for treating female sexual dysfunction which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, and

     2) a compound selected from the group consisting of a cyclic guanosine 3′

,5′

-monophosphate elevator.

46. A pharmaceutical composition of claim 45 wherein said cyclic guanosine 3′

,5′

-monophosphate elevator is a PDE_V phosphodiesterase inhibitor.

47. A pharmaceutical composition of claim 46 wherein said PDE_V phosphodiesterase inhibitor is 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sufonyl]-4-methylpiperazine citrate salt.

48. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, and

     2) an estrogen optionally with a progestin.

49. A pharmaceutical composition of claim 48 wherein the estrogen is Premarin®

.

50. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, and

     2) a compound selected from the group consisting of Prostaglandins;

Apomorphine;

Oxytocin modulators;

α

-2 Adrenergic antagonists;

Androgens;

selective androgen receptor modulators (SARMs);

bupropion;

Vasoactive intestinal peptide (VIP);

Neutral endopeptidase inhibitors (NEP); and

Neuropeptide Y receptor antagonists (NPY).

51. A pharmaceutical composition for treating female sexual dysfunction which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors;

     2) a compound that is a melanocortin receptor agonist; and

     3) a compound selected from the group consisting of a cyclic guanosine 3′

,5′

-monophosphate elevator.

52. A pharmaceutical composition of claims 51 wherein said cyclic guanosine 3′

,5′

-monophosphate elevator is a PDE_V phosphodiesterase inhibitor.

53. A pharmaceutical composition of claim 52 wherein said PDE_V phosphodiesterase inhibitor is 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sufonyl]-4-methylpiperazine citrate salt.

54. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors;

     2) a compound that is a melanocortin receptor agonist; and

     3) an estrogen optionally with a progestin.

55. A pharmaceutical composition of claim 54 wherein the estrogen is Premarin®

.

56. A pharmaceutical composition which comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors;

     2) a compound that is a melanocortin receptor agonist; and

     3) a compound selected from the group consisting of Prostaglandins;

Apomorphine;

Oxytocin modulators;

α

-2 Adrenergic antagonists;

Androgens;

selective androgen receptor modulators (SARMs);

bupropion;

Vasoactive intestinal peptide (VIP);

Neutral endopeptidase inhibitors (NEP); and

Neuropeptide Y receptor antagonists (NPY).

57. A pharmaceutical composition that comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, which compound is useful to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasms;

     2) a compound that is a melanocortin receptor agonist; and

     3) a second compound useful to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasms.

58. A pharmaceutical composition that comprises 1) a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors, which compound is useful to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasm; and

     2) a second compound useful to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasms.

59. A kit to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasms comprising:

a) a first pharmaceutical composition comprising a compound that attenuates the binding of agouti-related protein to melanocortin receptors, but does not attenuate the binding of α

-melanocyte stimulating hormone to melanocortin receptors;

b) a second pharmaceutical composition comprising a second compound useful to treat sexual arousal disorder, treat vaginismus, enhance libido more than normal or increase the frequency or intensity of orgasms;

c) a container for the first and second compositions.