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Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity

a melanocortin-4 receptor and selective linear peptide technology, applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems of increasing the risk of skin cancer, increasing the risk of adrenal tissue carcinoma, and presenting a significant burden on the health care system, so as to improve the mc4-r agonist activity and the effect of treating or preventing obesity

Inactive Publication Date: 2005-10-27
CHEN LI +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds of formulae I, II and III as well as Penta-Adpc-(D)Phe-Arg-Trp-Gly-NH2 and Penta-Ape-(D)Phe-Arg-Trp-Gly-NH2 are agonists of the MC4-R. It is known that agonists of MC4-R activity cause reduction of food intake in a mouse model of human obesity. Therefore the compounds of formula I are useful in the treatment or prevention of obesity.
All of the compounds of formulae I, II and III exemplified below as well as Penta-Adpc-(D)Phe-Arg-Trp-Gly-NH2 and Penta-Ape-(D)P

Problems solved by technology

This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone.
Agonism of the MC1-R receptor results in stimulation of the melanocytes which causes eumelanin and increases the risk for cancer of the skin.
Stimulation of MC2-R activity can result in carcinoma of adrenal tissue.
Because of their different functions, simultaneous agonism of the activities of multiple melanocortin receptors has the potential of causing unwanted side effects.

Method used

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  • Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity
  • Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity
  • Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Fmoc-1-amino-4-phenylcyclohexane-1-carboxylic acid (Fmoc-Apc-OH)

Step 1:

To a solution of 4-phenylcyclohexanone (10.0 g, 57.5 mmol) in ethanol (100 mL) and water (33 mL) in a glass pressure bottle, were added ammonium carbonate (33 g, 344 mmol, 6 equiv.) and potassium cyanide (5.6 g, 86.2 mmol, 1.5 equiv.). The mixture was heated at 80-90° C. for 24 hrs. The cooled reaction mixture was added to icy water (400 ml) and stirred vigorously for 30 min. The resulting precipitate was suction filtered, washed thoroughly with water and dried to yield the hydantoin as a white solid (14.0 g, 100% yield). 1H NMR (DMSO-d6): 8.63 (s, 1H), 7.23-7.36 (m, 4), 7.15 (m, 1), 2.50 (m, 1H), 2.10 (m, 1H), 1.85 (d, 1H) and 1.55-1.80 (m, 6H).

Step 2:

The hydantoin (10.0 g) was suspended in aqueous NaOH (6N, 350 mL) and heated at 130° C. for 2-3 days. Upon the completion of the hydrolysis, the reaction mixture was neutralized with conc. HCl to slightly acidic (pH ˜6). The resulting slurr...

example 2

Preparation of Fmoc-1-amino-4-(4-methoxyphenyl)cyclohexane-1-carboxylic acid (Fmoc-4-MeOApc-OH)

Step 1:

A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodomethane (4.9 mL, 11.2 g, 78.6 mmol, 3 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H20 and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-methoxyphenyl)cyclohexanone (5.34 g, 100%). 1HNMR(CDCl3) 7.16 (dt, 2H), 6.87 (dt, 2H), 3.78 (s, 3H), 2.99 (tt, 1H), 2.47-2.53 (m, 4H), 2.20 (m, 2H) and 1.83-1.98 (m, 2H); MS (electrospray) m / e, 205 (M+1)+, Calcd for C13H16O2, 204.

Step 2:

To a solution of the ketone (3.86 g, 18.9 mmol) in ethanol (50 mL) and water (15 mL) in a glass pressure bottle, were added ammonium carbonate (14.5 g, 151 mmol, 8 equiv.) and po...

example 3

Preparation of Fmoc-1-amino-4-(4-ethoxyphenyl)cyclohexane-1-carboxylic acid (Fmoc-4-EtOApc-OH)

Step 1:

A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodoethane (10.5 mL, 20.5 g, 131 mmol, 5 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-ethoxyphenyl)cyclohexanone (5.74 g, 100%). 1H NMR (CDCl3) 7.15 (dt, 2H), 6.86 (dt, 2H), 4.02 (q, 2H), 2.99 (tt, 1H), 2.46-2.54 (m, 4H), 2.16-2.24 (m, 2H), 1.83-2.00 (m, 2H) and 1.41 (t, 3H); MS (electrospray) m / e, 219 (M+1)+, Calcd for C14H18O2, 218.

Step 2:

To a solution of the ketone (4.15 g, 19.01 mmol) in ethanol (50 mL) and water (15 mL) in a glass pressure bottle, were added ammonium carbonate (14.5 g, 151 mmo...

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Abstract

Peptides of formulae I, II and III that selectively activate melanocortin-4 (MC-4) receptor activity.

Description

BACKGROUND OF THE INVENTION Obesity is widely recognized as a serious health problem for the developed countries, and has reached epidemic status in the United States. More than 50% of the U.S. population is considered overweight, with >25% diagnosed as clinically obese and at considerable risk for heart disease, non-insulin dependent diabetes mellitus (NIDDM), hypertension, and certain cancers. This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone. Strategies for treating obesity include reducing food intake or enhancing the expenditure of energy. It has been demonstrated that, when injected into the third ventricle of the brain or intraperitoneally, a cyclic heptapeptide analog of α-melanocyte stimulating hormone (αMSH) having melanocortin-4 receptor (MC4-R) agonist activity caused long lasting inhibition of food intake in mice. This effect was reversible when...

Claims

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Application Information

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IPC IPC(8): A61K38/08A61P3/04A61K38/00A61P5/00A61P43/00C07K1/04C07K5/107C07K5/117C07K7/02C07K7/06C07K14/68
CPCA61K38/00C07K14/68C07K7/06C07K5/1016A61P3/04A61P43/00A61P5/00
Inventor CHEN, LICHEUNG, ADRIAN WAI-HINGCHU, XIN-JIEDANHO, WALEEDSWISTOK, JOSEPHYAGALOFF, KEITH ALAN
Owner CHEN LI
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