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

• Published in: Journal of medicinal chemistry 1998-10, Vol.41 (22), p.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: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Capillary Permeability - drug effects; Capsaicin; Cell Line; Crystallography, X-Ray; Guinea Pigs; Humans; Injections, Intravenous; Medical sciences; Models, Molecular; Molecular Conformation; Naphthyridines - administration & dosage; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Neurokinin-1 Receptor Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Stereoisomerism; Trachea - blood supply; Trachea - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980042m

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.