Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 1. Identification of the 4-quinolinecarboxamide framework

Journal of Medicinal Chemistry
G A GiardinaD W Hay

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 K...Continue Reading

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Citations

Jun 23, 2005·Journal of Biomedical Science·Yi-Ruu LinMing-Huan Chan
Oct 9, 2002·Progress in Neuro-psychopharmacology & Biological Psychiatry·Rafaela L Ribeiro, Thereza C M De Lima
Nov 17, 2001·Bioorganic & Medicinal Chemistry·I ChujoM Kasai
Jul 3, 2013·Nature Reviews. Endocrinology·Robert P Millar, Claire L Newton
Sep 12, 2015·Journal of Medicinal Chemistry·Margaret E OlsonDaniel A Harki
Jul 5, 2005·Expert Opinion on Investigational Drugs·P GeppettiC Bertrand
Aug 13, 2005·IDrugs : the Investigational Drugs Journal·D G Lloyd, M J Meegan
Mar 11, 2017·Bioorganic & Medicinal Chemistry·Patrick HocheggerRobert Weis
Oct 11, 2017·Expert Opinion on Therapeutic Patents·Haider BehbehaniThoraya A Farghaly
Sep 29, 2018·Minerva ginecologica·Claire L NewtonRobert P Millar
Oct 23, 2019·Acta Crystallographica. Section E, Crystallographic Communications·Sonia HayaniYoussef Kandri Rodi
Oct 21, 2016·Chemistry, an Asian Journal·Haojie MaGuosheng Huang

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