Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-07-16
2001-09-04
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C514S018700, C530S329000, C530S330000, C530S331000
Reexamination Certificate
active
06284735
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to melanocortin receptors and more specifically to the treatment of sexual dysfunction using melanocortin receptor 3 ligands.
2. Background Information
Sexual dysfunction can be due to several physiological, as well as psychological, factors. In males, erectile dysfunction can be associated with diseases such as diabetes mellitus, syphilis, alcoholism, drug dependency, hypopituitarism and hypothyroidism. Erectile dysfunction can also be caused by vascular and neurogenic disorders, or be a side effect of drugs such as hypertensives, sedatives, tranquilizers and amphetamines. In all, erectile dysfunction is estimated to affect up to 10 million men in the United States, with its incidence increasing with age up to 25% of men at age 65.
While various pharmaceutical treatments are commercially available or being developed, the underlying physiological bases for sexual dysfunction are not well understood. Attention has recently been drawn to melanocortin (MC) receptors, which are a group of cell surface proteins that mediate a variety of physiological effects. The MC receptors have been implicated in the regulation of adrenal gland function such as production of the glucocorticoid cortisol and aldosterone, control of melanocyte growth and pigment production, thermoregulation, immunomodulation and analgesia. Five distinct MC receptors have been cloned, although the specific role of each MC receptor is still unclear.
Certain compounds, termed “melanocortins” have been found to bind MC receptors, causing the activity of the receptors to increase or decrease. These melanocortins include melanocyte-stimulating hormones (MSH) such as &agr;-MSH, &bgr;-MSH and &ggr;-MSH, as well as adrenocorticotropic hormone (ACTH). Other compounds may bind as ligands to MC receptors, increasing or decreasing the activity of the receptors.
Thus, there is a need for compounds that can affect the activity of specific MC receptors that are involved with sexual dysfunction. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention provides a method for treating sexual dysfunction, such as erectile dysfunction or sexual arousal disorder, with a compound having the eneric formula X
1
-X
2
-(D)Phe-Arg-(D)Trp-X
3
. A particularly useful compound is HP-228, which has the formula Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
.
The invention also provides methods for selecting melanocortin receptor-3 ligands by determining whether a compound modulates the activity of MC-3 as an agonist or antagonist. These methods can be used to screen compound libraries for ligands to treat sexual dysfunction and other MC-3-associated conditions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for treating sexual dysfunction. The term “sexual dysfunction” herein means any condition that inhibits or impairs normal sexual function, including coitus. However, the term need not be limited to physiological conditions, but may include psychogenic conditions or perceived impairment without a formal diagnosis of pathology.
In males, sexual dysfunction includes erectile dysfunction. The term “erectile dysfunction” or “impotence” means herein the inability or impaired ability to attain or sustain an erection that would be of satisfactory rigidity for coitus. Sexual dysfunction in males can also include premature ejaculation and priapism, which is a condition of prolonged and sometimes painful erection unrelated to sexual activity, often associated with sickle-cell disease.
In females, sexual dysfunction includes sexual arousal disorder. The term “sexual arousal disorder” means herein a persistent or recurrent failure to attain or maintain the lubrication-swelling response of sexual excitement until completion of sexual activity. Sexual dysfunction in females can also include inhibited orgasm and dyspareunia, which is painful or difficult coitus.
The method for treating sexual dysfunction comprises the step of administering to the subject an effective dose of the compound
X
1
-X
2
-(D)Phe-Arg-(D)Trp-X
3
wherein
R
1
is H, COCH
3
, C
2
H
5
, CH
2
Ph, COPh, COO-t-butyl, COOCH
2
Ph, CH
2
CO-(polyethylene glycol) or A;
R
2
is H, COCH
3
, C
2
H
5
or CH
2
Ph;
R
3
is a linear alkyl group having 1 to 6 carbon atoms or a branched or cyclic alkyl group having 3 to 6 carbon atoms;
R
4
is (CH
2
)
m
—CONH
2
, (CH
2
)
m
—CONHR
1
or (CH
2
)
m
—CONHA;
R
5
is OH, OR
3
, NH
2
, SH, NHCH
3
, NHCH
2
Ph or A;
R
6
is H or R
3
;
R
7
is H, COCH
3
, C
2
H
5
, CH
2
Ph, COPh, COO-t-butyl, COOCH
2
Ph or CH
2
CO-(polyethylene glycol);
Ph is C
6
H
5
; m is 1, 2 or 3; n is 0, 1, 2 or 3; Y
1
and Y
2
are independently hydrogen atoms, or are taken together to form a carbonyl or thiocarbonyl; and A is
These peptide compounds are characterized in part by the core structures (D)Phe-Arg-(D)Trp or His-(D)Phe-Arg-(D)Trp and are described in U.S. Pat. No. 5,420,109, issued May 30, 1995, and U.S. Pat. No. 5,726,156, issued Mar. 10, 1998.
Particular compounds can be selected by further defining one or more of the individual variables in the generic formula above. The variable X
1
can be norleucine or Ac-norleucine; or even norvaline, Ac-norvaline, leucine, Ac-leucine, isoleucine or Ac-isoleucine. The variable X
2
can be Gln-His or His. The variable X
3
can be Gly or Gly-NH
2
. The variable R
1
can be H, C
2
H
5
or CH
2
Ph. The variables R
1
and R
2
can be COCH
3
or H independently. The variable R
5
can be NH
2
. The variable R
5
can be covalently bound to X
1
, forming a cyclic peptide.
A particularly useful compound is HP-228, which has the formula Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
. HP-228 can be synthesized as described in Example I.A. The effectiveness of HP-228 in treating sexual dysfunction such as erectile dysfunction is demonstrated in Example II.
Other useful compounds can have the (D)Phe of the formula be iodinated in the para position. Thus, a useful compound is HP-467, which has the formula Ac-Nle-Gln-His-(para-iodo-(D)Phe)-Arg-(D)Trp-Gly-NH
2
. HP-467 can be prepared as further described in Example I.B.
Other specific compounds useful in the method of the invention include
(D) Phe-Arg-(D)Trp
Ac-(D)Phe-Arg-(D)Trp
(D)Phe-Arg-(D)Trp-NH
2
Ac-(D)Phe-Arg-(D)Trp-NH
2
(cyclohexyl)Gly-Gln-His-(D)Phe-Arg-(D)Trp-Gly
Ac-(cyclohexyl)Gly-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
cyclo(His-(D)Phe-Arg-(D)Trp)
Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
His-(D)Phe-Arg-(D)Trp-Gly
His-(D)Phe-Arg-(D)Trp-Gly-NH
2
Ac-His-(D)Phe-Arg-(D)Trp-NH
2
His-(D)Phe-Arg-(D)Trp-OH
His-(D)Phe-Arg-(D)Trp
His-(D)Phe-Arg-(D)Trp-NH
2
Ac-His-(D)Phe-Arg-(D)Trp-OH
Ac-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-OH
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-OC
2
H
5
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH-NH
2
Ac-Nle-Asn-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
Ac-Nle-Asn-His-(D)Phe-Arg-(D)Trp-Gly-OH
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NHCH
2
CH
2
Ph
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NHCH
2
Ph
Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
Ac-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH
2
Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-NH
2
Ac-His-(D)Phe-Arg-(D)Trp(CH
2
)-(NAc)Gly-NH
2
His-(D)Phe-Arg-(D)Trp(CH
2
)-(NAc)Gly
Amino acids are indicated by their commonly known three-letter code. Nle is the three-letter code for norleucine. The prefix (D)-designates an amino acid having the D-configuration, as opposed to the naturally occurring L-configuration. Where no specific configuration is indicated, a skilled artisan would understand the amino acid to be an L-amino acid. Finally, Ph indicates a phenyl group (C
6
H
5
).
A skilled artisan would know that the choice of amino acids or amino acid analogs incorporated into the compound will depend in part on the specific physical, chemical or biological characteristics required of the compound. Such characteristics can be determined by the route of administration and the desired location of action.
Selective modification of the reactive groups also can impart desirable characteristics
Girten Beverly E.
Tuttle Ronald R.
Campbell & Flores LLP
Lion Bioscience AG
Russel Jeffrey E.
LandOfFree
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