NOVEL, POTENT, AND ORALLY-ACTIVE SUBSTANCE-P ANTAGONISTS - SYNTHESIS AND ANTAGONIST ACTIVITY OF N-BENZYLCARBOXAMIDE DERIVATIVES OF PYRIDO[3,4-B]PYRIDINE

A series of 4-phenylisoquinolone derivatives were synthesized and eval uated for NK1 (substance P) antagonist activity. Highly potent antagon ists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discover ed from the structure-activity relationship studies on the isoquinolon e-urea lead la. Optimization of the activity in this series resulted i n the development of henyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamide s (30) which are highly potent orally active NK1 antagonists. Among th e compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]7,8-dihydro -N, 7-dimethyl-8-oxo-5-(substituted phenyl)6-pyrido[3,4-b]pyridinecarb oxamides (30a,f,g) showed excellent antagonist activities with IC50 va lues (in vitro inhibition of [I-125]- BH-SP binding in human IM-9 cell s) 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 o ral administration with ED(50) values of 0.068-0.17 mg/kg. Conformatio nal studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.