Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N, 7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK(1) antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C((9))-position, (aR,9R)-7-[3, 5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1, 7]naphthyridine-6,13-dione [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C((9))-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl(3)). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC(50) (inhibition of [(125)I]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR, 9R)-8b was ca. 750-fold higher than that of its enantiomer (aS, 9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C((6))(=O)-N((7))-CH(2)Ar moiety is important for NK(1) receptor recognition. The NK(1) antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK(1) antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-8-oxo-5- (substituted phenyl)-6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [125I]-BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED50 values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

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.

1. To investigate the kinetics of ophidian l-amino acid oxidase, V and K(m) were determined for phenylalanines that were substituted in every ring position with groups of various size and reactivity, and for a few ring-substituted tryptophans and histidines. The venom of one representative from each of three major classes of poisonous snakes, Naja melanoleuca, Vipera russelli and Crotalus adamanteus, served as a source of the ophidian l-amino acid oxidase. Both crude and crystalline enzyme from the venom of C. adamanteus were tested. 2. The introduction of a benzene ring into glycine and alanine caused some increase of V and a very marked depression of K(m). 3. With the exception of fluorine, residues in the ortho position of phenylalanine led to a decrease of V. The rates induced by various substitutions follow the pattern: meta >/= para >/= ortho. Within the halogen series, the effects become more pronounced with increasing atomic number. 4. Ring substitution in heterocyclic amino acids also affected the V values markedly. For methyl-substituted tryptophans the pattern was: 5-methyl >/= 6-methyl >/= 4-methyl. In a few instances ring substitution accounts for a considerable elevation of V, as shown for beta-quinol-4-ylalanine and its 6-methoxy derivative. 5. The kinetic constants appear to be unaffected by relatively high concentrations of the corresponding d-amino acids. 6. A general principle that permits a uniform interpretation of a vast body of information is suggested. It is based on the assumption that most substrates form not only eutopic but also dystopic complexes with the enzyme. The latter, in contrast with the former, do not permit the formation of reaction products. K values for eutopic and dystopic complexes are computed. Similar concepts have been presented to elucidate the action of alpha-chymotrypsin (Hein & Niemann, 1962) and of monoamine oxidase.

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