title: 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.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com
authors.forename: Donald S
authors.initials: DS
authors.lastname: Middleton
authors.forename: A Roderick
authors.initials: AR
authors.lastname: MacKenzie
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Newman
authors.forename: Martin
authors.initials: M
authors.lastname: Corless
authors.forename: Andrew
authors.initials: A
authors.lastname: Warren
authors.forename: Allan P
authors.initials: AP
authors.lastname: Marchington
authors.forename: Barry
authors.initials: B
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001384:Azetidines; D001682:Biological Availability; D002463:Cell Membrane Permeability; D006801:Humans; D020128:Inhibitory Concentration 50; D010599:Pharmacokinetics; D010879:Piperazines; D010881:Piperidones / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C416764:4-(1-(2-(1-(cyclopropylmethyl)-3-(3,4-dichlorophenyl)-6-oxo-3-piperidyl)ethyl)azetidin-3-yl)-1-piperazine sulfamide; D001384:Azetidines; D010879:Piperazines; D010881:Piperidones; D018041:Receptors, Neurokinin-2