title: Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: identification of 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds.
abstract: Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.
authors.affiliation: Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. mmeyers8@slu.edu
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
authors.forename: Scott A
authors.initials: SA
authors.lastname: Long
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pelc
authors.forename: Jane L
authors.initials: JL
authors.lastname: Wang
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bowen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Walker
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Schweitzer
authors.forename: Heather M
authors.initials: HM
authors.lastname: Madsen
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Tenbrink
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonald
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.forename: Susan
authors.initials: S
authors.lastname: Foltin
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D000099252:Fatty Acid Amide Hydrolases; C569541:1-oxa-8-azaspiro(4.5)decane; C569540:7-azaspiro(3.5)nonane