title: Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase.
abstract: A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address: jkeith@its.jnj.com.
authors.forename: John M
authors.initials: JM
authors.lastname: Keith
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Jones
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Pierce
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Seierstad
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Palmer
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Karbarz
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Scott
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Wennerholm
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Chang
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Brown
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Rynberg
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.affiliation: Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
mesh_terms: D000284:Administration, Oral; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001384:Azetidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D003500:Cyclization; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001384:Azetidines; D003959:Diamines; D006571:Heterocyclic Compounds; D013141:Spiro Compounds; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C000592754:JNJ-42119779
keywords: Covalent inhibitor; FAAH; Hydrolase; Spirocycles