Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB 223412)

Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK- 3 receptor antagonist 14, with regard to potential metabolic instability of the eater moiety and affinity and selectivity for the human neurokinin-3 ( hNK-3) receptor, is described. The eater functionality could be successfull y replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24 ). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 bin ding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of h alogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SE 2 23412, hNK-3-CHO binding K-i = 1.4 nM) and 55 (3-NHz, hNK-3-CHO binding K-i = 1.2 nM) were the most potent compounds of this series. Selectivity studi es versus the other neurokinin receptors (hNK-8-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, w ith no affinity for the hNK-1 at concentrations up to 100 mu M. In vitro st udies demonstrated that 53 is a potent functional antagonist of the hNK-3 r eceptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cell s stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-ind uced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy -2-phenylquinoline-4-carboxamide (53, SE 223412) may serve as a pharmacolog ical tool in animal models of disease to assess the functional and pathophy siological role of the NK-3 receptor and to establish therapeutic indicatio ns for non-peptide NK-3 receptor antagonists.