Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine

• Published in: Journal of medicinal chemistry Vol. 38; no. 16; pp. 3106 - 3120
• Main Authors: Natsugari, Hideaki, Ikeura, Yoshinori, Kiyota, Yutaka, Ishichi, Yuji, Ishimaru, Takenori, Saga, Osamu, Shirafuji, Hideo, Tanaka, Toshimasa, Kamo, Izumi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.08.1995; Amer Chemical Soc
• Subjects: Administration, Oral; Amino Acid Sequence; Animals; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Guinea Pigs; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Miscellaneous; Molecular Sequence Data; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridines - chemistry; Pyridines - pharmacology; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Substance P - antagonists & inhibitors; Urea - analogs & derivatives; Urea - chemistry; NONPEPTIDE ANTAGONIST; PHARMACOLOGICAL PROPERTIES; CONSTRICTION; CP-96,345; EXTRAVASATION; NEUROKININ-1 RECEPTOR; BINDING-SITES; NK1 RECEPTOR ANTAGONIST; BRAIN; DISCOVERY; Human; Isoquinoline derivatives; NK1 receptor; Nitrogen heterocycle; Rodentia; Lactam; Oral administration; In vitro; Pyridine derivatives; In vivo; Vertebrata; Biological fixation; Mammalia; Guinea pig; Structure activity relation; Nonpeptide compound; Animal; Bicyclic compound; Organic amide; Antagonist; Chemical synthesis; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00016a014

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 la. 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 [I-125]- BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED(50) 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 ED(50) 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.