From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolines: a new class of orally bioavailable mGluR1 antagonists.
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.
Di Fabio
Romano
R
GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
Micheli
Fabrizio
F
Alvaro
Giuseppe
G
Cavanni
Paolo
P
Donati
Daniele
D
Gagliardi
Tatiana
T
Fontana
Gabriele
G
Giovannini
Riccardo
R
Maffeis
Micaela
M
Mingardi
Anna
A
Tranquillini
Maria Elvira
ME
Vitulli
Giovanni
G
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
D000700:Analgesics; D002243:Carbolines; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1