Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA. daniel.w.kung@pfizer.com
Daniel W
DW
Kung
Steven B
SB
Coffey
Ryan M
RM
Jones
Shawn
S
Cabral
Wenhua
W
Jiao
Michael
M
Fichtner
Philip A
PA
Carpino
Colin R
CR
Rose
Richard F
RF
Hank
Michael G
MG
Lopaze
Roger
R
Swartz
Hou Tommy
HT
Chen
Zachary
Z
Hendsch
Bruce
B
Posner
Christopher F
CF
Wielis
Brian
B
Manning
Jeffrey
J
Dubins
Ingrid A
IA
Stock
Sam
S
Varma
Mary
M
Campbell
Demetria
D
DeBartola
Rachel
R
Kosa-Maines
Stefanus J
SJ
Steyn
Kim F
KF
McClure
D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D054314:Drug Inverse Agonism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001384:Azetidines; D010880:Piperidines; D054440:Receptors, Ghrelin; C082735:azetidine; C032727:piperidine