Substance P antagonists

The reacdon of y-nitrobiitenoate v/ith aldehydes and ketones in the presence of ammonium acetate gives 3-nitropiperidines. This reacdon is used for synthesis of CP-99,994, a highly potent substance P antagonist fScherae 10.23. ... 

The 2(lH)-pyrazinone system has received increased interest in the past two decades by both synthetic and biological research, due to its presence in a variety of natural and non-natural products as well as pharmacologically active compounds. The easy and diverse methods for the generation of this versatile scaffold make it a prime choice for the current pharmaceutical research hke thrombin inhibitors, substance P antagonists, etc. The rich 1,4-azadiene... 

One final mechanism that has recently shown promise for antidepressant effects appears distinct from all of the monoamine systems. A study published in 1998 demonstrated that a substance P antagonist (MK-869) had antidepressant effects in humans (Kramer et al. 1998). Substance P is localized to many areas of the brain that are involved in emotional processing, including the amygdala, dentate gyrus, subiculum, nucleus accumbens, striatum, locus coeruleus and periaqueductal grey (Kramer... 

Kamel AM, Zandi KS, Massefski WW. 2003. Identification of the degradation product of ezlopitant, a non-peptidic substance P antagonist receptor, by hydrogen deuterium exchange, electrospray ionization tandem mass spectrometry (ESI/MS/MM) and nuclear magnetic resonance (NMR) spectroscopy. J Pharm Biomed Anal 31 1211. 

Folkers K, Hakanson R, Horig J, Xu JC, Leander S (1984) Biological evaluation of substance P antagonists. Br J Pharmacol 83 449-456... 

The intramolecular Diels-Alder reaction of l-(A -a -alkenyl)-2(l//)-pyrazinones generates m-[l,7]naphthyridines in good yields (Scheme 62) <2001TL7397>. This method has been used in the development of a r-[l,7]naphthyr-idine-based scaffold on which to build a type VI external /3-turn mimic <2003EJ01868>, and for the synthesis and conformational analysis of [l,7]naphthyridine-based substance P antagonist analogues <2003T4721>. 

Argyropoulos, S. V. and Nutt, D. J. Substance P antagonists novel agents in the treatment of depression, Exp. Opin. Invest. Drugs 2000, 9, 1871-1875. 

Diener, H. C. (RPR100893-201 migraine study group) Substance P antagonist RPR100893-201 is not effective in human migraine attacks. 6 Int. Headache Res. Sem. Nov. 17-19 Copenhagen, Denmark 1995. 

U.S.A.) Preparation of 2-diphenylmethyl-3-benzylaminoquinuclidines as substance P antagonists, W09221677. 

Morimoto, H., Murai, M., Maeda, Y., Yamaoka, M., Nishikawa, M., Kiyotoh, S., Fujii, T. FK224, a novel cyclopeptide substance P antagonist with NKi and NK2 receptor selectivity, J. Pharmacol. Exp. Ther. 1992, 262, 398-402. 

Radhakrishnan, V. and Henry, J. L. Novel substance P antagonist, CP-96345, blocks responses of cat spinal dorsal horn neurons to noxious cutaneous stimulation and to substance P, Neurosci. Lett. 1991, 132, 39-43. 

On the other hand, suggestions that substance P antagonists may have improved mood, if not pain, in migraine patients led to controlled trials of such drugs in patients with depression. Although these are still early days and not all studies confirm antidepressant effects of substance P antagonists, the possibility that such... 

More recently, a Ti-TADDOLate catalyst was found useful for a similar asymmetric transformation, and this reaction has been successfully applied to the asymmetric synthesis of the potent, non-peptidic, NKl-selective, substance P antagonist RPR 107880 [59] (Eq. 8A.35). 

Adell A. Antidepressant properties of substance P antagonists relationship to monoaminergic mechanisms ... 

A novel application of this chemistry to a short synthesis of enantiomeri-cally pure 2-hydroxymorpholine 136, an intermediate in the synthesis of the substance P antagonist Apprepitant 138 (Scheme 7.18), was reported by a group from Merck [64]. Interestingly, despite the initial formation of a complex diastereo-meric mixture, compound 136 was isolated in high yield and enantioselectivity via a crystallization-induced diastereoselection and could be completely isomerized to 137, a precursor to 138. 

Zhao ZZ, Qin X-Z, Wu A, Yuan Y. Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist. J Pharm Sci 2004 93(8) 1957-1961. 

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