title: Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.
abstract: There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Analisa D
authors.initials: AD
authors.lastname: Thompson
authors.forename: Julie R
authors.initials: JR
authors.lastname: Field
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lindsley
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.forename: Satyawan
authors.initials: S
authors.lastname: Jadhav
authors.forename: Rocio
authors.initials: R
authors.lastname: Zamorano
authors.forename: Jim
authors.initials: J
authors.lastname: Bogenpohl
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.forename: Ryan
authors.initials: R
authors.lastname: Morrison
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D006224:Cricetinae; D003412:Cricetulus; D006220:Haloperidol; D006801:Humans; D066298:In Vitro Techniques; D054833:Isoindoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D000978:Antiparkinson Agents; D054833:Isoindoles; C569674:N-(3-chloro-4-(bicyclo(2.2.1)hept-5-ene-1,3-dioxo-1H-isoindol-1-yl)phenyl)picolinamide; D010848:Picolinic Acids; D018094:Receptors, Metabotropic Glutamate; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4