Melanocortin receptor ligands

Details Melanocortin receptor ligands Melanocortin receptor ligands

2000-03-29

2003-09-02

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

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S329000, C530S330000, C514S011400, C514S016700

Reexamination Certificate

active

06613874

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new melanocortin receptor ligands. These ligands are cyclic peptide analogs that preferably exhibit selectivity for the MC-4 and/or the MC-3 receptors relative to the other melanocortin receptors (in particular the MC-1 receptor).
BACKGROUND OF THE INVENTION
Melanocortin peptides (melanocortins) are natural peptide hormones in animals and man that bind to and stimulate MC-receptors. Examples of melanocortins are &agr;-MSH (melanocyte stimulating hormone), &bgr;-MSH, &ggr;-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is mainly known for its ability to regulate peripheral pigmentation (Eberle 1988), whereas ACTH is known to induce steroidoneogenesis (Simpson and Waterman, 1988). The melanocortin peptides also mediate a number of other physiological effects. They are reported to affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, brain blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual activity, penile erection, blood glucose levels, intrauterine fetal growth, food motivated behavior, as well as other events related to parturition.
ACTH and the various MSH peptides share the tetrapeptide core His-Phe-Arg-Trp. All of the peptides are derived from the proteolytic processing of the pro-peptide pre-opiomelanocortin (POMC). In the past several years, five distinct melanocortin receptor subtypes have been identified. These MC receptors belong to the class of 7 transmembrane domain G-protein coupled receptors. The five MC receptors, termed MC-1, MC-2, MC-3, MC-4 and MC-5, all couple in a stimulatory fashion to cAMP. Of these, the MC-2 receptor is the ACTH receptor, whereas the others constitute subtypes of MSH receptors. The MC-1receptor is present on melanocytes and melanoma. The MC-2 receptor is present predominantly in the adrenal gland. The mRNA for the MC-3 receptor has been found in the brain, as well as in placental and gut tissues (Gantz et al. 1993a, Desamaud et al. 1994, Roselli Rehfuss et al. 1993). The MC-4 receptor has been found primarily in the brain (Gantz et al. 1993b; Mountjoy et al 1994). The MC-5 receptor is expressed in the brain, as well as in several peripheral tissues (Chhajlani et al 1993; Gantz et al 1994; Griffon et al 1994; Labbu et al. 1994; Barrett et al. 1994; Fathi et al.1995). More recent data from humans indicate that all of the cloned MC-receptors have a wider tissue distribution (Chhajlani, 1996) than originally thought.
As discussed above, the members of the melanocortin receptor family can be differentiated on the basis of their tissue distribution. Both the MC-4 and MC-3 receptors have been localized to the hypothalamus, a region of the brain believed to be involved in the modulation of feeding behavior. Compounds showing selectivity for the MC-4/MC-3 receptors have been shown to alter food intake following intracerebroventricular and peripheral injection in rodents. Specifically, agonists have been shown to reduce feeding, while antagonists have been shown to increase feeding. See, Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”,
Nature
, 385(6612), pp. 165-8 (Jan. 9, 1997).
The role of the MC-4 receptor subtype has been more clearly defined in the control of eating and body weight regulation in mammals. See, e.g., Huszer, D. et al., “Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice”,
Cell
, pp. 131-141 (1997); Klebig, M. L. et al., “Ectopic Expression of the Agouti Gene in Transgenic Mice Causes Obesity, Features of Type II Diabetes, and Yellow Fur”,
Proc. Natl Acad Sci
., Vol. 92, pp. 4728-32 (1995); Karbon, W. et al., “Expression and Function of Argt, a Novel Gene Related to Agouti”,
Abstract from the Nineteenth Annual Winter Neuropeptide Conference
(1998); Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”,
Nature
, Vol. 385, pp. 165-168 (1997); Seely, R. J., “Melanocortin Receptors in Leptin Effects”,
Nature
, Vol. 390, p. 349 (1997); Comuzzie, A. G., “A Major Quantitative Trait Locus Determining Serum Leptin Levels and Fat Mass is Located on Human Chromosome 2
”, Nat. Gen
., Vol. 15, pp. 273-276 (1997); Chagnon, Y. C. et al., “Linkage and Association Studies Between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Quebec Family Study”,
Mol. Med
., Vol 3(10), pp. 663-673 (1997); Lee, F. and Huszar, D, “Screening Methods for Compounds Useful in the Regulation of Body Weight”, World Patent Publication WO 97/47316 (1997); and Shutter, J. R. et al., “Hypothalamic Expression of ART, a Novel Gene Related to Agouti, is Up-Regulated in Obese and Diabetic Mutant Mice”,
Gen
. &
Dev
. Vol. 11, pp. 593-602 (1997). Stimulation of the MC-4 receptor by its endogenous ligand, CCMSH, produces a satiety signal and may be the downstream mediator of the leptin satiety signal. It is believed that by providing potent MC-4 receptor agonists, appetite may be suppressed and weight loss benefits may be achieved.
Applicants have discovered a class of compounds that surprisingly have high affinity for the MC-4 and/or the MC-3 receptor subtypes, and that are typically selective for these MC receptors relative to the other melanocortin receptor subtypes, particularly the MC-1 subtype. It is therefore an object of this invention to provide chemical compounds that activate or antagonize the MC-4 and/or the MC-3 receptor subtypes. It is a further object of the invention to provide means for administration of said compounds to animals or man. Still other objects of the invention will be evident from the following disclosure of the invention.
DISCLOSURE OF THE INVENTION
Applicants have discovered certain structural requirements for a class of cyclic peptide analogs that are ligands for receptors of the MC-4 and/or the MC-3 subtype. The structural requirements constitute an optimal ring size of the peptide analog cycle at the proper location in the analog, as is described below. Thus, the present invention relates to a cyclic peptide analog having a structure according to Formula (I):
wherein
(A) each of m, n, and q is independently selected from 0 to about 4 and p is from 0 to about 5;
(B) X, which represents the four substituents on the phenyl ring other than E and (CH
2
)
m
, is independently selected from hydrogen; halo; OR
8
; —SR
8
; —NR
8
R
8′
; —N(R
8
)SO
2
R
8″
; —SO
2
R
8″
; —SO
2
—NR
8
R
8′
; alkyl; alkene; alkyne; cyano; nitro; CF
3
; aryl; heteroaryl; cycloalkyl; heterocycloalkyl; and —(CH
2
)
r
—PO
2
HR
14
where r is 0 to about 10 and R
14
is selected from —OH, hydrogen and alkyl; where each R
8
and R
8′
is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl and R
8″
is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or two X moieties can together form a fused ring with the depicted phenyl ring;
(C) E is selected from hydrogen; halo; —OR
13
; —SR
13
; —NR
13
R
13′
; —N(R
13
)SO
2
R
13″
; —SO
2
R
13″
; —SO
2
—NR
13
R
13′
; —(CH
2
)
r
—PO
2
HR
15
where r is 0 to about 10 and R
5
is selected from —OH, hydrogen and alkyl; alkyl; alkene; alkyne; cyano; nitro; CF
3
; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; provided that when each X is hydrogen, E is not hydrogen; where each R
13
and R
13′
is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl and R
13″
is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(D) Z is one or more substituents independently selected from hydrogen, hydroxy, halo, thiol, —OR
9
, —SR
9
, —NR
9
R
9′
, alkyl,

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