title: The synthesis and biological evaluation of quinolyl-piperazinyl piperidines as potent serotonin 5-HT1A antagonists.
abstract: 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.
authors.affiliation: Chemical Sciences, Pfizer Global Research and Development, Princeton, New Jersey 08543-8000, USA. wchilders@yahoo.com
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Havran
authors.forename: Magda
authors.initials: M
authors.lastname: Asselin
authors.forename: James J
authors.initials: JJ
authors.lastname: Bicksler
authors.forename: Dan C
authors.initials: DC
authors.lastname: Chong
authors.forename: George T
authors.initials: GT
authors.lastname: Grosu
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Shen
authors.forename: Magid A
authors.initials: MA
authors.lastname: Abou-Gharbia
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Bach
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Natasha
authors.initials: N
authors.lastname: Kagan
authors.forename: Teresa
authors.initials: T
authors.lastname: Kleintop
authors.forename: Ronald
authors.initials: R
authors.lastname: Magolda
authors.forename: Vasilios
authors.initials: V
authors.lastname: Marathias
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Annmarie L
authors.initials: AL
authors.lastname: Sabb
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
authors.forename: Susan H
authors.initials: SH
authors.lastname: Aschmies
authors.forename: Chad
authors.initials: C
authors.lastname: Beyer
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Mark
authors.initials: M
authors.lastname: Day
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Brian
authors.initials: B
authors.lastname: Platt
authors.forename: Claudine
authors.initials: C
authors.lastname: Pulicicchio
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Smith
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Sukoff-Rizzo
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Sullivan
authors.forename: Adedayo
authors.initials: A
authors.lastname: Adedoyin
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
mesh_terms: 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
chemical_list: 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