title: Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.
abstract: Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2receptor. The hydroxyacetophenone scaffold is a second series of mGlu2PAMs we have identified. This series of molecules are potent mGlu2potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: blanco_maria@lilly.com.
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Blanco
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Dana R
authors.initials: DR
authors.lastname: Benesh
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Knobelsdorf
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Khilevich
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Guillermo S
authors.initials: GS
authors.lastname: Cortez
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Fese
authors.initials: F
authors.lastname: Mokube
authors.affiliation: Array BioPharma Inc., Boulder, CO, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.affiliation: Array BioPharma Inc., Boulder, CO, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Groendyke
authors.affiliation: Array BioPharma Inc., Boulder, CO, USA.
authors.forename: Fredrik P
authors.initials: FP
authors.lastname: Marmsater
authors.affiliation: Array BioPharma Inc., Boulder, CO, USA.
authors.forename: Tony P
authors.initials: TP
authors.lastname: Tang
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Clemens-Smith
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Muhlhauser
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Swanson
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: John
authors.initials: J
authors.lastname: Catlow
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Schkeryantz
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D015394:Molecular Structure; D051381:Rats; D018077:Receptors, Leukotriene / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018077:Receptors, Leukotriene; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2; C083169:leukotriene D4 receptor
keywords: Allosteric modulators; CysLT1; Metabotropic glutamate receptor; Migraine; PAMs; mGlu(2)