Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity.
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK. s.roughley@vernalis.com
Stephen D
SD
Roughley
Helen
H
Browne
Alba T
AT
Macias
Karen
K
Benwell
Teresa
T
Brooks
Jalanie
J
D'Alessandro
Zoe
Z
Daniels
Sarah
S
Dugdale
Geraint
G
Francis
Ben
B
Gibbons
Terance
T
Hart
Timothy
T
Haymes
Guy
G
Kennett
Sean
S
Lightowler
Natalia
N
Matassova
Howard
H
Mansell
Angela
A
Merrett
Anil
A
Misra
Anthony
A
Padfield
Rachel
R
Parsons
Robert
R
Pratt
Alan
A
Robertson
Heather
H
Simmonite
Kiri
K
Tan
Steven B
SB
Walls
Melanie
M
Wong
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001384:Azetidines; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C082735:azetidine