- Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554
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The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-ph
- Banno, Yoshihiro,Miyamoto, Yasufumi,Sasaki, Mitsuru,Oi, Satoru,Asakawa, Tomoko,Kataoka, Osamu,Takeuchi, Koji,Suzuki, Nobuhiro,Ikedo, Koji,Kosaka, Takuo,Tsubotani, Shigetoshi,Tani, Akiyoshi,Funami, Miyuki,Tawada, Michiko,Yamamoto, Yoshio,Aertgeerts, Kathleen,Yano, Jason,Maezaki, Hironobu
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p. 4953 - 4970
(2011/10/04)
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- Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyridopyridine
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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-pyridopyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists.Among the compounds synthesized, N--7,8-dihydro-N,7-dimethyl-8-oxo-5-(substituted phenyl)-6-pyridopyridinecarboxamides (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 adiministration 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.
- Natsugari, Hideaki,Ikeura, Yoshinori,Kiyota, Yutaka,Ishichi, Yuji,Ishimaru, Takenori,et al.
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p. 3106 - 3120
(2007/10/02)
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- Heterocyclic amine, derivatives, their production and use
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A novel heterocyclic amine derivative of the general formula: STR1 wherein a ring A and a ring B stand independently for an optionally substituted benzene ring, Z° stands for O or S or STR2 stands for --CH2 --, X stands for O, S or NR1/su
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