title: From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolines: a new class of orally bioavailable mGluR1 antagonists.
abstract: Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
authors.affiliation: GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavanni
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gagliardi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Riccardo
authors.initials: R
authors.lastname: Giovannini
authors.forename: Micaela
authors.initials: M
authors.lastname: Maffeis
authors.forename: Anna
authors.initials: A
authors.lastname: Mingardi
authors.forename: Maria Elvira
authors.initials: ME
authors.lastname: Tranquillini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D002243:Carbolines; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1