Neuropeptide Y (NPY), a 36 amino acid peptide neurotransmitter, is a member of the pancreatic polypeptide class of neurotransmitters/neurohormones. NPY is widely distributed throughout the central nervous system and is one of the most conserved peptide in evolution, suggesting an important role in the regulation of basic physiological functions. Investigations to date have implicated NPY in the pathophysiology of a number of diseases including feeding disorders, seizures, anxiety, diabetes, hypertension, cancer (e.g., breast and pancreatic cancer), nasal congestion, sexual dysfunctions, congestive heart failure, and intestinal dysfunctions. At least 6 NPY receptor subclasses have been identified and cloned to date, with two of these subclasses, NPY-1 and NPY-5, thought to be the most important receptor subtypes modulating food intake and energy expenditure. See, Balasubramaniam, A., “Clinical potentials of neuropeptide Y family of hormones,” Am. J. of Surgery, 183, 430-434 (2002) for a review.
Various animal studies have shown that activation of neuropeptide Y receptors is related to stimulation of consummatory behavior, Flood and Morley Peptides, 10, 963-966 (1989), Leibowitz and Alexander, Peptides, 12, 1251-1260 (1991), and Stanley et al. Peptides, 13, 581-587 (1992), and to vasoconstriction, Wahlestedt et al. Regul. Peptides, 13, 307-318 (1986), McCauley and Westfall J. Pharmacol. Exp. Ther. 261, 863-868 (1992), and Grundemar et al. Br. J. Pharmacol 105, 45-50 (1992).
Further, Grundemar and Hakanson TiPS, May 1994 [Vol. 15], 153-159, state that in animals, NPY is a powerful stimulus of food intake and inducer of vasoconstriction leading to hypertension. They also point out that low levels of NPY are associated with loss of appetite. The reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
Hence, agents capable of blocking NPY binding at these receptor subtype(s) should have utility in a number of feeding disorders including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorders including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well other indications for treatment where blockade of NPY activity is beneficial.
In addition, both pre-clinical and clinical evidence have suggested that NPY, together with its receptors, may have a direct implication in several psychiatric disorders, including depression and related illnesses. NPY-like immunoreactivity and NPY receptors are expressed through out the brain, with varying concentrations being found throughout the limbic system. Such brain structures have been repeatedly implicated in the modulation of emotional processing, as well as in the pathogenesis of depressive disorders. For a review, see, Redrobe, J. P., et al., “Neuropeptide Y (NPY) and Depression: From Animal Studies to the Human Condition,” Life Sciences, 71, 2921-2937 (2002).
EP0759441 and U.S. Pat. No. 5,576,337 report physiological disorders related to any excess of NPY.
WO 99/01128 discloses certain NPY-5 receptor mediators useful for treating feeding disorders such as obesity and bulima as well as certain cardiovascular diseases such as essential hypertension.
Although NPY-5 receptor antagonists are known, there still exists a need for additional antagonists that may be useful in the treatment of diseases modulated by NPY-5 receptor antagonists especially in light of the important role NPY receptors play in the regulation of the basic physiological functions discussed above.