Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(substituted)-1-azetidinyl]-ethyl}-2-piperidones. Part 2: Improving oral absorption.

Abstract A series of piperidone analogues of 1b – q , seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671 1a , possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of 1n , which demonstrated equivalent pharmacology and metabolic stability to 1a , and greatly improved oral absorption as assessed in rat PK studies.