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

• Published in: Journal of medicinal chemistry 1997-06, Vol.40 (12), p.1794-1807
• Main Authors: Giardina, Giuseppe A. M, Sarau, Henry M, Farina, Carlo, Medhurst, Andrew D, Grugni, Mario, Raveglia, Luca F, Schmidt, Dulcie B, Rigolio, Roberto, Luttmann, Mark, Vecchietti, Vittorio, Hay, Douglas W. P
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; CHO Cells; Cricetinae; Humans; Hydrogen Bonding; Medical sciences; Molecular Structure; Muscle Contraction - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptide Fragments - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - metabolism; Rabbits; Receptors, Neurokinin-3 - antagonists & inhibitors; Receptors, Neurokinin-3 - genetics; Receptors, Neurokinin-3 - metabolism; Recombinant Proteins - metabolism; Stereoisomerism; Structure-Activity Relationship; Substance P - analogs & derivatives; Substance P - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960818o

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-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding K i = 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 K i = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding K i = >100 μM). 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 b = 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.