The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists.
As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.
Childers
Wayne E
WE
Chemical Sciences, Pfizer Global Research and Development, Princeton, New Jersey 08543-8000, USA. wchilders@yahoo.com
Havran
Lisa M
LM
Asselin
Magda
M
Bicksler
James J
JJ
Chong
Dan C
DC
Grosu
George T
GT
Shen
Zhongqi
Z
Abou-Gharbia
Magid A
MA
Bach
Alvin C
AC
Harrison
Boyd L
BL
Kagan
Natasha
N
Kleintop
Teresa
T
Magolda
Ronald
R
Marathias
Vasilios
V
Robichaud
Albert J
AJ
Sabb
Annmarie L
AL
Zhang
Mei-Yi
MY
Andree
Terrance H
TH
Aschmies
Susan H
SH
Beyer
Chad
C
Comery
Thomas A
TA
Day
Mark
M
Grauer
Steven M
SM
Hughes
Zoe A
ZA
Rosenzweig-Lipson
Sharon
S
Platt
Brian
B
Pulicicchio
Claudine
C
Smith
Deborah E
DE
Sukoff-Rizzo
Stacy J
SJ
Sullivan
Kelly M
KM
Adedoyin
Adedayo
A
Huselton
Christine
C
Hirst
Warren D
WD
D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
C550157:5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline; D016564:Amyloid beta-Protein Precursor; D000928:Antidepressive Agents; D018697:Nootropic Agents; D010879:Piperazines; D010880:Piperidines; D011804:Quinolines; D058829:Serotonin 5-HT1 Receptor Antagonists; D005473:Fluoxetine; D012701:Serotonin; D000109:Acetylcholine