Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
2001-01-16
2004-02-17
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C514S011400, C514S017400, C514S018700, C530S330000
Reexamination Certificate
active
06693165
ABSTRACT:
BACKGROUND OF THE INVENTION
Melanocortin peptides or melanotropins, &agr;-MSH, &bgr;-MSH, &ggr;-MSH and ACTH, are involved in many physiological functions in vertebrates, mammals and in man. They regulate skin pigmentation and steroid production, modulate immune responses and learning processes, influence energy balance, growth and regeneration of nerves, and several other functions as well.
Five human receptors are known which interact with melanotropins, hMC-1R to hMC-5R. The receptors are seven-helix transmembrane-spanning receptors and belong to the superfamily of G protein-coupled receptors; their activation leads to elevation of cAMP. The melanocortin receptors 1, 3, 4 and 5 recognize &agr;-MSH, &bgr;-MSH and &ggr;-MSH, while melanocortin receptor 2 recognizes only ACTH.
Considerable attention has recently focused on melanocortin receptors 3 and 4 that are widely expressed in the central nervous system, and also on melanocortin receptor 5, found in the brain and in various peripheral tissues. The physiological role of hMC-3R and hMC-5R is not well defined, although hMC-5R has recently been implicated in control of lipid and pheromone production in exocrine glands. Rapidly growing pharmacological and genetic evidence suggests that hMC-4R is involved in regulation of the energy balance and body weight in rodents. The role of MC-4R in regulation of food intake and body weight is supported by results obtained from agonist/antagonist administration in rats and from murine genetics. Intraventricular administration of the agonist MTII reduced food intake and conversely, the antagonist SHU9119 increased food intake and body weight. Mice genetically deficient in the melanocortin receptor 4 develop obesity. It could be anticipated therefore that compounds active at MC-4R might be useful in the treatment of eating disorders.
Melanocortin receptor 4 appears to play a role in other physiological functions as well, namely in controlling grooming behavior, erection and blood pressure. The natural hormones, melanotropins, however, have relatively low affinity for hMC3-5R and are not particularly selective. In order to differentiate the physiological role of melanocortin receptor 4 from that of other melanocortin receptors in the brain, in particular from MC-3R, potent and selective antagonists are necessary. The synthetic ligands available at present do not distinguish between the melanocortin receptors. A frequently used research tool is the SHU9119 peptide, a potent antagonist at melanocortin receptors 3 and 4, and an agonist at melanocortin receptor 5. SHU9119 has been extensively studied in vitro and in vivo; injection of this peptide stimulates food intake in rats. A similar lactam derivative, the peptide MTII is a potent but non-selective agonist at hMC3-5R.
Recently several peptides, which are cyclized via disulfide bridges, have been reported as antagonists of the &agr;-MSH responses at MC-3R and MC-4R, and the most potent and MC-4R selective antagonists are HS014, HS024 and HS028. HS014 and HS028 are partial agonists at melanocortin receptors 1 and 5, whereas at the same receptors, HS024 is an antagonist. In rats these antagonists increase food intake and body weight. While SHU9119, HS014, HS024 and HS028 are potent antagonists at MC-4R, they are not sufficiently selective for MC-4R over the other MC receptors. Thus there remains a need to provide for potent and selective antagonists of MC-4R that will allow for the differentiation of the physiological roles of the MC-4 receptor from those of other melanocortin receptors. Such selective antagonists may also be useful as therapeutic agents for the diagnosis, treatment or prevention of diseases and disorders mediated through the MC-4 receptor, more particularly eating disorders related to underweight, cachexia or anorexia of any cause in humans.
SUMMARY OF THE INVENTION
The present invention provides cyclic peptides that are potent and selective antagonists of the human melanocortin-4 receptor. These compounds are useful as research tool for the determination of the physiological roles of the MC-4 receptor, as well as for the diagnosis, treatment or prevention of disorders or diseases mediated through the MC-4 receptor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of the formula I
wherein
D represents that the amino acid is an D-amino acid;
m, n, p, q and r are independently 0 or 1, with the proviso that when p is 1, then either q is 1 or n+m is 1, and when p is 0, then q is 0 and m and n are each 1;
s is an integer from 1 to 4;
R
1
and R
2
are each hydrogen, or R
1
and R
2
together represent methylene, or R
1
and R
2
together represent a bond;
R
3
is H, Ac, Nle or N—Ac-Nle, with the proviso that when R
3
is N—Ac-Nle, r is 0;
R
4
is —(CH
2
)
3
NH
2
or 4-imidazolyl;
R
5
is selected from 1- or 2-naphthyl, 3-benzothienyl, phenyl optionally substituted with a group selected from halogen, C
1-4
alkyl, and C
1-4
alkoxy;
R
6
is —(CH
2
)
2
CH
3
, —(CH
2
)
2
NHC(═NH)NH
2
or —(CH
2
)
3
NH
2
; and
R
7
is 3-indolyl, 1- or 2-naphthyl, or phenyl optionally substituted with a halogen; or a salt thereof.
In one embodiment of formula I, r is 0. In another embodiment p and q are each 0. In yet another embodiment s is 3 or 4. In a preferred embodiment, r, p and q are each 0, s is 3 or 4, and m+n is 2.
In another embodiment of formula I, R
1
and R
2
are each hydrogen.
In another embodiment of formula I, R
5
is selected from 2-naphthyl, benzothienyl, and 4-substituted phenyl where said substituent is C
1-4
alkyl, C
1-4
alkoxy or halogen. A subset within this embodiment provides compounds where R
5
is selected from 2-naphthyl and 4-substituted phenyl where said substituent is t-butyl, methoxy, chloro, iodo or fluoro.
In yet another embodiment of formula I, R
6
is —(CH
2
)
2
NHC(═NH)NH
2
.
In another embodiment of formula I, R
7
is selected from 3-indolyl, 2-naphthyl and 4-halophenyl. A subset within this embodiment provides compounds where R
7
is 3-indolyl.
Compounds of formula Ia represent a subset of formula I:
where R
1
, R
2
and s are as defined under formula I; R
5
is selected from 2-naphthyl, benzothienyl, and 4-substituted phenyl where said substituent is C
1-4
alkyl, C
1-4
alkoxy or halogen; and R
7
is 3-indolyl, 2-naphthyl or 4-halophenyl.
As used in the application, Ac is acetyl, Arg is arginine, His is histidine, D-(2′)-Nal is D-3-(2-naphthyl)alanine, Nle is norleucine, Trp is tryptophan. The amino acid components of formula I are L-amino acids unless specified otherwise.
Compounds of the present invention are potent and selective antagonists of the melanocortin-4 receptor, and as such are useful as analytical research tool for the study of the physiological roles of the melanocortin-4 receptor. In addition, compounds of the present invention are useful for the diagnosis, treatment and prevention of diseases and disorders that may benefit from the blocking of the MC-4 receptor, in particular diseases and disorders related to eating disorders.
For analytical and diagnostic purposes the compounds of the present invention can be used in radioactive form, including radioactive labels. In particular the compounds of the invention may be manufactured so as to incorporate radioactive iodine or tritium, or any other suitable radio nuclide. Such a radioactively labeled compound can be used in radioligand binding for the the quantification of specific melanocortin receptors, for the analysis of dissociation constant (K
i
s or K
d
s) of drugs competing with specific subtypes of melanocortin receptors, and for the localization of MC-receptors in tissues and tissue sections e.g. by use of receptor autoradiographic techniques. Principles of radioligand binding and receptor autoradiography are well known in the art. As an alternative the compound may be labeled with any other type of label that allows detection of the substance, e.g. a fluorescent label or biotin, and the resulting compound be used for the similar purpose as the radioactively labeled compound.
The compo
Low Christopher S. F.
Lukton David
Merck & Co. , Inc.
Rose David L.
Yang Mollie M.
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