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 in | Journal of medicinal chemistry Vol. 41; no. 22; pp. 4232 - 4239 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
22.10.1998
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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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. |
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Bibliography: | istex:FB6023FEF98A1D706E0D826F6C056F7707FB7ABE ark:/67375/TPS-CT729181-X ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm980042m |