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

Donald S Middleton; A Roderick MacKenzie; Sandra D Newman; Martin Corless; Andrew Warren; Allan P Marchington; Barry Jones

doi:10.1016/j.bmcl.2005.05.134

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

Bioorg Med Chem Lett. 2005 Sep 1;15(17):3957-61. doi: 10.1016/j.bmcl.2005.05.134.

Authors

Donald S Middleton¹, A Roderick MacKenzie, Sandra D Newman, Martin Corless, Andrew Warren, Allan P Marchington, Barry Jones

Affiliation

¹ Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com

PMID: 16039119
DOI: 10.1016/j.bmcl.2005.05.134

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.

MeSH terms

Administration, Oral
Animals
Azetidines
Biological Availability
Cell Membrane Permeability
Humans
Inhibitory Concentration 50
Pharmacokinetics
Piperazines
Piperidones / chemical synthesis
Piperidones / pharmacokinetics*
Piperidones / pharmacology
Pulmonary Artery / drug effects
Rabbits
Rats
Receptors, Neurokinin-2 / antagonists & inhibitors
Structure-Activity Relationship

Substances

4-(1-(2-(1-(cyclopropylmethyl)-3-(3,4-dichlorophenyl)-6-oxo-3-piperidyl)ethyl)azetidin-3-yl)-1-piperazine sulfamide
Azetidines
Piperazines
Piperidones
Receptors, Neurokinin-2