Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(substituted)-1-azetidinyl]-ethyl}-2-piperidones. Part 2: Improving oral absorption |
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| Authors: | Middleton Donald S MacKenzie A Roderick Newman Sandra D Corless Martin Warren Andrew Marchington Allan P Jones Barry |
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| Affiliation: | Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com |
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| 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. |
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