4-Acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a Novel Class of Non-Brain-Penetrant Histamine H3 Receptor Antagonists

摘要

A series of ketopiperazines were prepared and evaluated for their activity as histamine H3 antagonists.From investigation of the tertiary basic center in the aminopropyloxyphenyl template,the 2(R)-methylpyrrolidine was identified as the most potent amine.In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine.The 4-fluorobenzyol,4-cyanobenzoyl,and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides.The PSA and log D values of these compounds suggested low brain penetration.The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450,indicating low drug-drug interaction potential.Compound 22i was identified as the best compound of this series based on its overall profile of high potency,selectivity,low brain penetration,lack of CYP450 inhibition,high oral bioavailability,and pharmacokinetic properties.