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

摘要: 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), discovered from the structure-activity relationship studies on isoquinolone-urea lead 1a. Optimization activity in this resulted development 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly orally active antagonists. Among 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 activities with IC50 values (in vitro inhibition [125I]-BH-SP binding human IM-9 cells) 0.21-0.34 nM ED50 vivo capsaicin-induced plasma extravasation guinea-pig trachea, iv) 0.017-0.030 mg/kg. These exhibited significantly upon oral administration 0.068-0.17 Conformational 30g indicated that two stable conformers quite similar to those CP-99,994.