New quinoline NK3 receptor antagonists with CNS activity

• Published in: Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.837-840
• Main Authors: SMITH, Paul W, WYMAN, Paul A, COGGON, Sara, MURKITT, Graham, SEARLE, Kirsten, THOMAS, David R, WATSON, Jeannette M, MARTIN, William, ZINING WU, DAWSON, Lee A, LOVELL, Peter, GOODACRE, Caroline, SERAFINOWSKA, Halina T, VONG, Antonio, HARRINGTON, Frank, FLYNN, Sean, BRADLEY, Daniel M, PORTER, Rod
• Format: Article
• Language: English
• Subjects: Amines - metabolism; Animals; Area Under Curve; Biological and medical sciences; Brain - metabolism; Central Nervous System - drug effects; Cerebral Cortex - embryology; Gerbillinae; Male; Medical sciences; Models, Chemical; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - metabolism; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-3 - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.005

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.