title: A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core.
abstract: A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.
authors.affiliation: Addex Therapeutics, 12 Chemin des Aulx, Plan-les-Ouates 1228, Geneva, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Duvey
authors.forename: Benjamin
authors.initials: B
authors.lastname: Perry
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bonnet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambeng
authors.forename: Delphine
authors.initials: D
authors.lastname: Charvin
authors.forename: Tansy
authors.initials: T
authors.lastname: Donovan-Rodrigues
authors.forename: Hasnaà
authors.initials: H
authors.lastname: Haddouk
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rocher
mesh_terms: D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000737:chemistry
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: Allosteric; Glutamate; Metabotropic; Pain; mGlu5