title: Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.
abstract: We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Chobanian
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Chioda
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Selena
authors.initials: S
authors.lastname: Fung
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lanza
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Raman K
authors.initials: RK
authors.lastname: Bakshi
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Dellureficio
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Belyk
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Shane W
authors.initials: SW
authors.lastname: Krska
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Makarewicz
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Martel
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Frey
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Bindhu
authors.initials: B
authors.lastname: Karanam
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Raul
authors.initials: R
authors.lastname: Alvaro
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Shuman
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Terebetski
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Mistry
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: McGowan
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenbach
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Alexander
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Shiao
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sullivan
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Immunology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
keywords: CNS; FAAH; Fatty acid amide hydrolase; MK-4409; enzyme; inflammatory pain; inhibitor; neuropathic pain; oxazole; pyrazole