New Amide Derivatives as Melanin-concentrating Hormone Receptor 1 Antagonists for the Treatment of Obesity

Abstract

Melanin-concentrating hormone (MCH) is a recently discovered central nervous system (CNS) target for treating obesity. Two novel series of amide derivatives were synthesized and evaluated biologically as MCH-R1 (melanin-concentrating hormone receptor 1) antagonists. The results showed that diphenyl substituents on the amide lead to better activity than biphenyl substituents.

Key words

Melanin-concentrating hormone, amide derivatives, biphenylamide, diphenylmide - Melanin-concentrating hormone receptor 1, antagonists - Obesity

• Literature

• 1 Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL. The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical char acterization. J Comp Neurol. 1992; 319: 218-245
• 2 Rossi M, Choi SJ, O’Shea D, Miyoshi MA, Ghatei SR, Bloom SR. Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology. 1997; 138: 351-355
• 3 Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998; 396: 670-673
• 4 Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J et al. Melanin-concentrating hormone overex-pression in transgenic mice leads to obesity and insulin resistance. J Clin Invest. 2001; 107: 379-386
• 5 Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, De-Leon J, Lagu B et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med. 2002; 8: 825-830
• 6 Chen Y, Hu C, Hsu CK, Zhang O, Bi C, Asnicar M et al. Tar geted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to dietinduced obesity. Endocrinology. 2002; 143: 2469-2477
• 7 Takekawa S, Asami A, Ishihara Y, Terauchi J, Kato K, Shimomura Y et al. T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol. 2002; 438: 129-135
• 8 Palani A, Shapiro S, McBriar MD, Clader JW, Greenlee WJ, Spar B et al. Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity. J Med Chem. 2005; 48: 4746-4749
• 9 Cheng YC, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC₅₀) of an enzymatic reaction. Bio-cheen. Pharmacol. 1973; 22: 3099-3108
• 10 www.chemicon.com [cited Feb 2008].