3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists

Journal of Medicinal Chemistry

Volumn 39, Issue 3, 1996, Pages 736-748

  Hipskind, Philip A ^a   Howbert, J Jeffry ^a,c   Bruns, Robert F ^a   Cho, Steven S Y ^a   Crowell, Thomas A ^a   Foreman, Mark M ^a   Gehlert, Donald R ^a   Iyengar, Smriti ^a   Johnson, Kirk W ^a   Krushinski, Joseph H ^a   Li, Dominic L ^a   Lobb, Karen L ^a   Mason, Norman R ^a   Muehl, Brian S ^a   Nixon, James A ^a   Phebus, Lee A ^a   Regoli, Domenico ^b   Simmons, Rosa M ^a   Threlkeld, Penny G ^a   Waters, Diane C ^a   Gitter, Bruce D ^a   more..

^a ELI LILLY AND COMPANY   (United States)

^b UNIVERSITÉ DE SHERBROOKE   (Canada)

^c Darwin Molecular Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2 DIACETAMIDOPROPANE DERIVATIVE; 2 [1 IMINO 2 (2 METHOXYPHENYL)ETHYL] 7,7 DIPHENYLPERHYDROISOINDOL 4 ONE; 2 BENZHYDRYL 3 (2 METHOXYBENZYLAMINO) 1 AZABICYCLO[2.2.2]OCTANE; 3 (1H INDOL 3 YL) 1 [N (2 METHOXYBENZYL)ACETYLAMINO] 2 [N [2 [4 (1 PIPERIDINYL) 1 PIPERIDINYL]ACETYL]AMINO]PROPANE; GUANINE NUCLEOTIDE BINDING PROTEIN; LANEPITANT; NEUROKININ A; NEUROKININ B; NOLPITANTIUM; SUBSTANCE P; TRYPTOPHAN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BINDING AFFINITY; GUINEA PIG; MOUSE; NONHUMAN; RACEMIC MIXTURE; RECEPTOR AFFINITY; SMOOTH MUSCLE CONTRACTION; STRUCTURE ACTIVITY RELATION; TRIGEMINUS GANGLION; VASODILATATION;

AMIDES; ANALGESICS; ANIMALS; ELECTRIC STIMULATION; ESTERS; GUINEA PIGS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MICE; RATS; RECEPTORS, NEUROKININ-1; SPECIES SPECIFICITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 13344283413     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950616c     Document Type: Article

References (60)

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31. Recently detailed accounts of tryptophan ester and amide SAR's have appeared. See: (a) MacLeod, A. M.; Merchant, K. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Swain, C. J.; Baker, R. N-Acyl-L-Tryptophan Benzyl Esters: Potent Substance P Receptor Antagonists. J. Med. Chem. 1993, 36, 2044-2045. (b) MacLeod, A. M.; Merchant, K. J.; Brookfield, F.; Kelleher, F.; Stevenson, G.; Owens, A. P.; Swain, C. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M.; Ball, R. G.; Baker, R. Identification of L-Tryptophan Derivatives with Potent and Selective Antagonist Activity at the NK-1 Receptor. J. Med. Chem. 1994, 37, 1269-1274. (c) Lewis, R. T.; MacLeod, A M.; Merchant, K. J.; Kelleher, F.; Sanderson, I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.; Hoogsteen, K. Tryptophan-Derived NK-1 Antagonists: Conformationally Constrained Heterocyclic Bioisosteres of the Ester Linkage. J. Med. Chem. 1995, 38, 923-933.
32. Recently detailed accounts of tryptophan ester and amide SAR's have appeared. See: (a) MacLeod, A. M.; Merchant, K. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Swain, C. J.; Baker, R. N-Acyl-L-Tryptophan Benzyl Esters: Potent Substance P Receptor Antagonists. J. Med. Chem. 1993, 36, 2044-2045. (b) MacLeod, A. M.; Merchant, K. J.; Brookfield, F.; Kelleher, F.; Stevenson, G.; Owens, A. P.; Swain, C. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M.; Ball, R. G.; Baker, R. Identification of L-Tryptophan Derivatives with Potent and Selective Antagonist Activity at the NK-1 Receptor. J. Med. Chem. 1994, 37, 1269-1274. (c) Lewis, R. T.; MacLeod, A M.; Merchant, K. J.; Kelleher, F.; Sanderson, I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.; Hoogsteen, K. Tryptophan-Derived NK-1 Antagonists: Conformationally Constrained Heterocyclic Bioisosteres of the Ester Linkage. J. Med. Chem. 1995, 38, 923-933.
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39. This trend has also been observed in the quinuclidine (see: Lowe, J. A.; Drozda, S. E.; Snider, R. M.; Longo, K. P.; Zorn, S. H.; Morrone, J.; Jackson, E. R.; McLean, S.; Bryce, D. K.; Bordner, J.; Nagahisa, A.; Kanai, Y.; Suga, O.; Tsuchiya, M. The Discovery of (2S,3S)-cis-2-(Diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2,2,2]- octan-3-amine as a Novel, Nonpeptide Substance P Antagonist J. Med. Chem. 1992, 35, 2591-2600) and triarylperhydroisoindole (Tabart, M. unpublished results) NK-1 antagonist SAR's.
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43. For discussions regarding this type of π/πi-nteraction, see: (a) Hunter, C. A.; Sanders, J. K. M. The Nature of π-π Interactions. J. Am. Chem. Soc. 1990, 112, 5525-5534. (b) Jorgensen, W. L.; Severance, D. L. Aromatic-Aromatic Interactions: Free Energy Profiles for the Benzene Dimer in Water, Chloroform and Liquid Benzene. J. Am. Chem. Soc. 1990, 112, 4768-4774. (c) Trost, B. M.; O'Krongly, D.; Belletire, J. L. A Model for Asymmetric Induction in the Diels-Alder Reaction. J. Am. Chem. Soc. 1980, 102, 7595-7596.
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58. 50 of 19 ng/kg, iv, was obtained in our labs for sumatriptan, an unrelated 5-HT agonist known to be active in this model. See: (a) Buzzi, M. G.; Moskowitz, M. A. The Trigemino-Vascular System and Migraine Pathol. Biol. 1992, 40, 313-317. (b) Buzzi, M. G.; Moskowitz, M. A. Evidence for 5-HT1B/1D Receptors Mediating the Antimigraine Effect of Sumatriptan and Dihydroergotamine Cephalalgia 1991, 10, 165-168.
59. This compound was obtained from its tert-butyl carbamate by treatment with 70% aqueous trifluoroacetic acid containing anisole by analogy with compound 21 using the above method B, steps 1 and 2.
60. See ref 26.