Over the last decade, major advances have been made in the understanding of the biology of the mammalian tachykinin neuropeptides. It is now well established that substance-P (1), neurokinin A (NKA) (2), and neurokinin B (NKB) (3), all of which share a common C-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2, (Nakanishi S., Physiol. Rev., 1987;67:117), are widely distributed throughout the periphery and central nervous system (CNS) where they appear to interact with at least three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3, (Guard S., et al., Neurosci. Int., 1991;18:149). Substance-P displays highest affinity for NK.sub.1 receptors, whereas NKA and NKB bind preferentially to NK.sub.2 and NK.sub.3 receptors, respectively. Recently, all three receptors have been clones and sequenced and shown to be members of the G-protein-linked "super family" of receptors (Nakanishi S., Annu. Rev. Neurosci., 1991;14:123). A wealth of evidence supports the involvement of tachykinin neuropeptides in a variety of biological activities including pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system (inflammatory pain), and neurogenic inflammation (Pernow B., Pharmacol. Rev., 1983;35:85). However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been severely hampered by a lack of selective, high affinity, metabolically stable tachykinin receptor antagonists that possess both good bioavailability and CNS penetration. Although several tachykinin receptor antagonists have been described (Tomszuk B. E., et al., Current Opinions in Therapeutic Patents, 1991;1:197), most have been developed through the modification and/or deletion of one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
However, since 1991, a number of high-affinity nonpeptide antagonists have been reported. Snider R. M., et al., (Science, 1991;251:435), and Garret C., et al., (Proc. Natl. Acad. Sci., 1991;88:10208), described CP-96,345 and RP 67580, respectively, as antagonists at the NK.sub.1 receptor, while Advenier C., et al., (Brit. J. Pharmacol., 1992;105:78), presented data on SR 48968 showing its high affinity and selectivity for NK.sub.2 receptors. More recently Macleod, et al., (J. Med. Chem., 1993;36:2044) have published on a novel series of tryptophan derivatives as NK.sub.1 receptor antagonists. It is of interest that most of the nonpeptide tachykinin receptor antagonists described to date arose, either directly or indirectly, out of the screening of large compound collections using a robust radioligand binding assay as the primary screen. Recently, FK 888, a "dipeptide" with high affinity for the NK.sub.1 receptor was described (Fujii J., et al., Neuropeptide, 1992;22:24). Only one NK.sub.3 receptor selective ligand, SR 142801, has been published on to date (Edmonds-Alt, et al., Life Sciences, 1995;56:27).
International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 cover certain nonpeptide tachykinin receptor antagonists.
NKB and also NK.sub.3 receptors are distributed throughout the periphery and central nervous system (Maggi, et al., J. Auton. Pharmacol., 1993;13:23). NKB is believed to mediate a variety of biological actions via the NK.sub.3 receptor including gastric acid secretion; appetite regulation; modulation of serotonergic, cholinergic, and dopaminergic systems; smooth muscle contraction and neuronal excitation. Recent publications descriptive of this art include Polidor, et al., Neuroscience Letts., 1989;103:320; Massi, et al., Neuroscience Letts., 1988;92:341, and Improta, et al., Peptides, 1991;12:1433. Due to its actions with dopaminergic (Elliott, et al., Neuropeptides, 1991;19:119), cholinergic (Stoessl, et al., Psycho. Pharmacol., 1988;95:502), and serotonergic (Stoessl, et al., Neuroscience Letts., 1987;80:321) systems, NKB may play a role in psychotic behavior, memory functions, and depression.
Accordingly, compounds capable of antagonizing the effects of NKB at NK.sub.3 receptors will be useful in treating or preventing a variety of disorders including pain, depression, anxiety, panic, schizophrenia, neuralgia, addiction disorders, inflammatory diseases; gastrointestinal disorders including colitis, Crohn's disease, inflammatory bowel disorder, and satiety; vascular disorders such as angina and migraine and neuropathological disorders such as Parkinsonism and Alzheimer's.
USPTO Backgrounds
USPTO Backgrounds