Identification of highly selective and potent orexin receptor 1 antagonists derived from a dual orexin receptor 1/2 antagonist based on the structural framework of pyrazoylethylbenzamide.

The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead ( 1 ) by installing a ( S )-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N -ethyl-5-fluoro- N -{(2 S )-1-[5-(4-fluorophenyl)-2 H -tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide ( 24 ), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC 50 of 2.01 nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2. [ABSTRACT FROM AUTHOR]