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 (1t), was shown to exist as a mixture of separable and stable (R)- and (S)-atropisomers (1t-A and 1t-B) originating from the restricted rotation around the -C(6)-C(=O)- bond; the antagonistic activities of 1t-A were ca. 6-13-fold higher than those of 1t-B. Analogues of 1t (3), which have (S)- and (R)-methyl groups at the benzylic methylene portion of 1t, 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 micrograms/kg (iv) and 67.7 micrograms/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 1t-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.
Pharmaceutical Research Division and Technology Development Department, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532, Japan.
Y
Y
Ikeura
Y
Y
Ishichi
T
T
Tanaka
A
A
Fujishima
M
M
Murabayashi
M
M
Kawada
T
T
Ishimaru
I
I
Kamo
T
T
Doi
H
H
Natsugari
D000284:Administration, Oral; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin; D002460:Cell Line; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D007275:Injections, Intravenous; D008958:Models, Molecular; D008968:Molecular Conformation; D009287:Naphthyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D013237:Stereoisomerism; D014132:Trachea / Q000098:blood supply / Q000187:drug effects
C115422:N-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide; C115421:N-(3,5-bis(trifluoromethyl)benzyl)-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide; D009287:Naphthyridines; D064729:Neurokinin-1 Receptor Antagonists; D002211:Capsaicin