title: Piperidinyl thiazole isoxazolines: A new series of highly potent, slowly reversible FAAH inhibitors with analgesic properties.
abstract: Fatty acid amide hydrolase (FAAH) is a membrane anchored serine hydrolase that has a principle role in the metabolism of the endogenous cannabinoid anandamide. Docking studies using representative FAAH crystal structures revealed that compounds containing a novel piperidinyl thiazole isoxazoline core fit within the ligand binding domains. New potential FAAH inhibitors were designed and synthesized incorporating urea, carbamate, alkyldione and thiourea reactive centers as potential pharmacophores. A small library of candidate compounds (75) was then screened against human FAAH leading to the identification of new carbamate and urea based inhibitors (Ki=pM and nM, respectively). Representative carbamate and urea based chemotypes displayed slow, time dependent inhibition kinetics leading to enzyme inactivation which was slowly reversible. However, evidence indicated that features of the mechanism of inactivation differ between the two pharmacophore types. Selected compounds were also evaluated for analgesic activity in the mouse-tail flick test.
authors.affiliation: E.I. Du Pont de Nemours and Company, Stine Haskell Research Center, 1090 Elkton Rd., Newark, DE 19711, USA. Electronic address: steve.o.pember@dupont.com.
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Pember
authors.affiliation: School of Behavioral and Brain Sciences, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA; University of Arizona, Department of Pharmacology, 1501 N. Campbell Ave., Tucson, AZ 85724, USA. Electronic address: glm140230@utdallas.edu.
authors.forename: Galo L
authors.initials: GL
authors.lastname: Mejia
authors.affiliation: School of Behavioral and Brain Sciences, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA; University of Arizona, Department of Pharmacology, 1501 N. Campbell Ave., Tucson, AZ 85724, USA. Electronic address: theodore.price@utdallas.edu.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: E.I. Du Pont de Nemours and Company, Stine Haskell Research Center, 1090 Elkton Rd., Newark, DE 19711, USA. Electronic address: robert.j.pasteris@dupont.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pasteris
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D010880:Piperidines; D013844:Thiazoles; D000099252:Fatty Acid Amide Hydrolases
keywords: Analgesia; Fatty acid amide hydrolase; Inactivation; Inhibition; Piperidinyl thiazole isoxazoline