| Summary: | Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT<sub>2C</sub> agonists. To improve selectivity for 5-HT<sub>2C</sub> over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds <b>10a</b> and <b>10f</b> as potent 5-HT<sub>2C</sub> agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine <b>10a</b> showed a highly agonistic effect on the 5-HT<sub>2C</sub> receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine <b>10a</b> could be considered a viable lead compound as a 5-HT<sub>2C</sub> selective agonist.
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