title: Novel, potent, and orally active substance P antagonists: synthesis and antagonist activity of N-benzylcarboxamide derivatives of pyrido[3,4-b]pyridine.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Natsugari
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeura
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyota
authors.forename: Y
authors.initials: Y
authors.lastname: Ishichi
authors.forename: T
authors.initials: T
authors.lastname: Ishimaru
authors.forename: O
authors.initials: O
authors.lastname: Saga
authors.forename: H
authors.initials: H
authors.lastname: Shirafuji
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: I
authors.initials: I
authors.lastname: Kamo
authors.forename: T
authors.initials: T
authors.lastname: Doi
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D011725:Pyridines; D013373:Substance P; D014508:Urea