Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyridopyridine

Article abstract of 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 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 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.