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