Compositions and methods for treatment of sexual dysfunction

Details Compositions and methods for treatment of sexual dysfunction Compositions and methods for treatment of sexual dysfunction

2002-01-04

2004-09-21

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Melanotropin or eledoisin; related peptides

C530S317000, C530S321000, C530S300000, C530S328000, C530S329000, C514S009100, C514S011400, C514S012200, C514S015800, C514S016700, C514S018700, C424S009100, C436S811000

Reexamination Certificate

active

06794489

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention (Technical Field)
The present invention relates to peptide constructs for the treatment of sexual dysfunction in animals, including both male erectile dysfunction and female sexual dysfunction, including methods and formulations for the use and administration of the same.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.
At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E
1
, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.
A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.
Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic &agr;-melanocyte-stimulating hormone (“&agr;-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al.,
J Urology
160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled
Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction
and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled
Stimulating Sexual Response in Females
. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled
Cyclic Analogs of Alpha
-
MSH Fragments
, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled
Linear Analogs of Alpha
-
MSH Fragments
. Melanotan-II is a peptide of the following formula:
Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.
In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo (p=0.0045). The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.
The minimum peptide fragment of native &agr;-MSH needed for erectile response is the central tetrapeptide sequence, His
6
-Phe
7
-Arg
8
-Trp
9
(SEQ ID NO:1). In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. Five distinct melanocortin receptor subtypes have been identified, called MC1-R through MC5-R, and of these MC3-R and MC4-R are believed to be expressed in the human brain. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it has been hypothesized that it involves the central nervous system, and probably binding to MC3-R and/or MC4-R.
Other peptides and constructs have been proposed which are ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled
Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same
, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled
Spiropiperidine Derivatives as Melanocortin Receptor Agonists.
Both cyclic and linear &agr;-MSH peptides have been studied; however, the peptides heretofore evaluated have had an amide or —NH
2
group at the carboxyl terminus. See, for example, Wessells H. et al.,
J Urology
, cited above; Haskell-Luevano C. et al.,
J Med Chem
40:2133-39 (1997); Schiöth H. B. et al.,
Brit J Pharmacol
124:75-82 (1998); Schiöth H. B. et al.,
Eur J Pharmacol
349:359-66 (1998); Hadley M. E. et al.,
Pigment Cell Res
9:213-34 (1996); Bednarek M. A. et al.,
Peptides
20:401-09 (1999); U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290; and, International Patent Applications PCT/US99/04111 and PCT/US98/03298. While significant research has been conducted in an effort to determine the optimal structure of &agr;-MSH peptides, including a variety of structure-function, agonist-antagonist, molecular modeling and pharmacophore studies, such studies have relied upon peptides with an art conventional —NH
2
group at the carboxyl terminus. Further, it has long been believed that biologically active neuropeptides, including &agr;-MSH peptides, are amidated, with an —NH
2
group at the carboxyl terminus, and that such amidation is required both for biological activity and stability. See, for example,
Metabolism of Brain Peptides
, Ed. G. O'Cuinn, CRC Press, New York, 1995, pp. 1-9 and 99-101.
SUMMARY OF THE INVENTION (DISCLOSURE OF THE INVENTION)
The invention relates to a peptide that is a free acid or pharmaceutically acceptable salt thereof that includes the sequence His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, homologs of His-Phe-Arg-Trp (SEQ ID NO:1) or

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