Axially Chiral N-Benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK1 Receptor Antagonists:  Determination of the Absolute Stereochemical Requirements

A potent and orally active NK1 antagonist, trans-N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1 t ), was shown to exist as a mixture of separable and stable (R)- and (S)-atropisomers (1 t -A and 1 t -B) originating from the res...

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Published inJournal of medicinal chemistry Vol. 41; no. 22; pp. 4232 - 4239
Main Authors Ikeura, Yoshinori, Ishichi, Yuji, Tanaka, Toshimasa, Fujishima, Akira, Murabayashi, Mika, Kawada, Mitsuru, Ishimaru, Takenori, Kamo, Izumi, Doi, Takayuki, Natsugari, Hideaki
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 22.10.1998
Amer Chemical Soc
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Summary:A potent and orally active NK1 antagonist, trans-N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1 t ), was shown to exist as a mixture of separable and stable (R)- and (S)-atropisomers (1 t -A and 1 t -B) originating from the restricted rotation around the −C(6)−C(O)− bond; the antagonistic activities of 1 t -A were ca. 6−13-fold higher than those of 1 t -B. Analogues of 1 t (3), which have (S)- and (R)-methyl groups at the benzylic methylene portion of 1 t , were prepared and separated into the diastereomeric atropisomers, 3a-A, 3a-B and 3b-A, 3b-B, in enantiomerically pure forms. Among the four isomers of 3, the (aR,S)-enantiomer (3a-A) exhibited the most potent antagonistic activities with an IC50 value of 0.80 nM (in vitro inhibition of [125I]BH-SP binding in human IM-9 cells) and ED50 values of 9.3 μg/kg (iv) and 67.7 μg/kg (po) (in vivo inhibition of capsaicin-induced plasma extravasation in guinea pig trachea), while the activity of the (aS,R)-enantiomer (3b-B) was the weakest with an IC50 value of 620 nM. The structure−activity relationships in this series of antagonists indicate that the (R)-configuration at the axial bond and the stacking (or stacking-like) conformation between the two phenyl rings as shown in 1 t -A and 3a-A are essential for high-affinity binding and suggest that the amide moiety functions as a hydrogen bond acceptor in the interaction with the receptor.
Bibliography:istex:FB6023FEF98A1D706E0D826F6C056F7707FB7ABE
ark:/67375/TPS-CT729181-X
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm980042m