title: Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.
abstract: Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.
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: Barbara A
authors.initials: BA
authors.lastname: Schweitzer
authors.forename: Mark V
authors.initials: MV
authors.lastname: Wilcox
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: Jeanne
authors.initials: J
authors.lastname: Rumsey
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Yang
authors.forename: Mark C
authors.initials: MC
authors.lastname: Walker
authors.forename: Satwik
authors.initials: S
authors.lastname: Kamtekar
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D000284:Administration, Oral; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001372:Aza Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D000099252:Fatty Acid Amide Hydrolases; C569542:PF-04862853