Identification and chemical synthesis of MDL 105,212, a non-peptide tachykinin antagonist with high affinity for NK1 and NK2 receptors

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 8, 1996, Pages 951-956

  Burkholder, Timothy P ^a   Kudlacz, Elizabeth M ^a   Le, Tieu Binh ^a   Knippenberg, Robert W ^a   Shatzer, Scott A ^a   Maynard, George D ^a   Webster, Mark E ^a   Horgan, Stephen W ^a  

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

2 BENZHYDRYL 3 (2 METHOXYBENZYLAMINO) 1 AZABICYCLO[2.2.2]OCTANE; MDL 104335; MDL 105212; NEUROKININ 1 RECEPTOR; NEUROKININ 2 RECEPTOR; NEUROKININ 3 RECEPTOR; PYRROLIDINE DERIVATIVE; SAREDUTANT; TACHYKININ RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CELL LINE; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; GUINEA PIG; HUMAN; HUMAN CELL; LUNG; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

EID: 0029873748     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00148-5     Document Type: Article

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15. Conformational searching using Sybyl software (Tripos force field and Gasteiger-Huckel charges) in combination with potential energy surface analysis and the local minima method of pharmacophore determination were used (David A. Demeter, Ph.D. Thesis, University of Cincinnati, 1994).
16. Additional low energy minima conformations of CP 96,345 which have a face to face stacking arrangement of the aromatic ring of the benzyl amine and one of the aromatic rings of the diphenylmethyl moiety overlap with low energy conformations of MDL 103,220. However, the hydrogen bond acceptor is not directed toward the same face of the molecule.
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18. 2 receptors in HSKR-1 cells. Each value is the mean of at least 3 determinations ± SEM unless otherwise noted. Receptor binding affinity has been determined by the experimental methods previously described (Kudlacz, E. M., Logan, D. E., Shatzer, S. A., Farrell, A. M., Baugh, L. E. Eur. J. Pharm. 1993, 241, 17).
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25. For details about the potent functional antagonism of MDL 105,212 in vitro and its activity in vivo as measured by the ability to antagonize respiratory effects produced in response to exogenously administered and endogenously released tachykinins see Kudlacz, E. M.; Shatzer, S. A.; Knippenberg, R. W.; Logan, D. E., Poirot, M.; van Giersbergen, P. L. M.; Burkholder, T. P. J. Pharmacol. Exp. Ther. 1996, in press.