title: 4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators.
abstract: 4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE=0.43), optimization of in vitro potency for this series reached a plateau around EC(50)=200 nM.
authors.affiliation: Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Hermogenes N
authors.initials: HN
authors.lastname: Jimenez
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Liu
authors.forename: Sang-Phyo
authors.initials: SP
authors.lastname: Hong
authors.forename: Michael S
authors.initials: MS
authors.lastname: Reitman
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Uberti
authors.forename: Maria D
authors.initials: MD
authors.lastname: Bacolod
authors.forename: Manuel
authors.initials: M
authors.lastname: Cajina
authors.forename: Megan
authors.initials: M
authors.lastname: Nattini
authors.forename: Michael
authors.initials: M
authors.lastname: Sabio
authors.forename: Darío
authors.initials: D
authors.lastname: Doller
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4