Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.

Abstract This Letter describes the asymmetric synthesis of the four stereoisomers ( 8a – 8d ) of a potent and highly selective histamine H 3 receptor (H 3 R) antagonist, 5-fluoro-2-methyl- N -[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl) phenyl]benzamide ( 1 ). The physico-chemical properties, in vitro H 3 R affinities and ADME of 8a – 8d were determined. Stereoisomer 8c (2 S ,3′ S ) displayed superior in vitro H 3 R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.