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

Bioorg Med Chem Lett. 2013 Jul 15;23(14):4044-7. doi: 10.1016/j.bmcl.2013.05.068. Epub 2013 May 30.

Abstract

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) 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 H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Brain / metabolism
  • Half-Life
  • Histamine Antagonists / chemical synthesis*
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / pharmacokinetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacokinetics
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H3 / metabolism
  • Stereoisomerism

Substances

  • 5-fluoro-2-methyl-N-(2-methyl-4-(2-methyl(1,3')bipyrrolidinyl-1'-yl)phenyl)benzamide
  • Benzamides
  • Histamine Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3
  • benzamide