New quinoline NK3 receptor antagonists with CNS activity.

Abstract 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.