Replacement of the quinoline system in 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists

Results from a medicinal chemistry approach aimed at replacing the quinolin e ring system in the potent and selective human neurokinin-3 (hNK-3) recept or antagonists 1-4 of general formula I are discussed. The data give furthe r insight upon the potential NK-3 pharmacophore. In particular, it is highl ighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. So me novel compounds maintained part of the binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, ap pears to be suitable for further modifications; it offers the option to int roduce electron-withdrawing groups at position 2 and 4, conferring on the r ing an overall electron-deficiency similar to that of the quinoline. (C) 19 99 Elsevier Science S.A. All rights reserved.