Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 1. Identification of the 4-Quinolinecarboxamide Framework

Abstract

A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds 33-76, prompted by chemical modifications of the prototype 4, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure-activity relationships (SARs) have been established. From SARs, (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding Ki = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding Ki = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding Ki = > 100 microM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a Kb = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.

Synthesis of 2‐(4‐Biphenylyl)quinoline‐4‐carboxylate and Carboxamide Analogs. New Human Neurokinin‐3 (hNK‐3) Receptor Antagonists

“…Based on the results of the biological screening of the carboxamide and ester candidates, one can conclude that the occurrence of an acidic amide is not important for their activities. This conclusion contradicts the previous proposal of Giardina et al [18] for analogous series. Introducing a large hydrophobic area at C-2 in the quinoline ring seemed to be irrelevant to the anticipated antagonistic activity of such types of compounds at the same receptor.Additionally, we suggest that the binding region of the antagonist may overlap with that of the agonist.The introduction of one bromine atom at C-6 of the quinoline ring would direct the bromo derivative (7b) towards the antagonistic region of the receptor and decrease the potency of senktide, whereas substituting the bromine with chlorine would direct the chloro compound (7c) towards the agonistic region and potentiate the potency of senktide via a synergistic mechanism.…”

“…In contrast, replacing the 6-bromo with a chloro atom as in 7c directed the activity, unexpectedly, towards the agonistic side (increase in response 18.39-2.5%) ( Table 1). The data also revealed that the carboxylate derivatives exerted appreciable antagonistic properties especially the aminoethyl carboxylate analog 9d (reduction in response 60.7-4.3%) ( Table 1).and its arylidene derivative 15b (reduction in response 55.28-6.5 %) ( These findings coincided with those of Giardina et al [18,20], who suggested that the 2-arylquinoline backbone would be considered as an essential pharmacophore for optimal fitting to the hNK-3 receptor. Based on the results of the biological screening of the carboxamide and ester candidates, one can conclude that the occurrence of an acidic amide is not important for their activities.…”

“…noticed [17].The proposed pharmacophore has demonstrated the significance of the lipophilic 2-phenyl moiety of the carboxyquinoline skeleton and the role of the exocyclic nitrogen as a hydrophilic hydrogen-bond acceptor center [18]. Recently, they proved that the 3-substituted-2-phenylquinoline-4-carboxamides 3 (Chart 1) were the most potent hNK-3 receptor antagonists [19].…”

Synthesis and further studies of chemical transformation of the 2-aryl-3-halogenoquinolin-4(1H)-one derivatives

“…However, the known nonbasic nature of amino group of the 4-amino-2-arylquinoline derivatives [17] prevented further derivatization to 4-Nsubstituted derivatives. In this investigation, we resorted to the application of an indirect method for the synthesis of N-substituted 2-aryl-3-halogenoquinoline derivatives.…”

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…Modifications to optimise these initial compounds led to the identification of talnetant (SB-223412), an orally-active, potent and selective TACR3 antagonist [156][157][158] . Analogs of talnetant with increased bloodbrain barrier permeability, SB-222200 159 and GSK256471 160 , or no blood-brain barrier permeability (SB-335375) 161 have since been described.…”