Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead.
Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.
Carlton
David L
DL
Department of Pharmaceutical Development, Physical Properties and Developability, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Collin-Smith
Lissa J
LJ
Daniels
Alejandro J
AJ
Deaton
David N
DN
Goetz
Aaron S
AS
Laudeman
Christopher P
CP
Littleton
Thomas R
TR
Musso
David L
DL
Morgan
Ronda J Ott
RJ
Szewczyk
Jerzy R
JR
Zhang
Cunyu
C
D016367:Baculoviridae / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005617:Chlorofluorocarbons, Methane / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009853:Omeprazole / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D018004:Receptors, Bombesin / Q000819:agonists* / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry
D001562:Benzimidazoles; D005617:Chlorofluorocarbons, Methane; D011725:Pyridines; D018004:Receptors, Bombesin; D013440:Sulfides; C107120:bombesin receptor subtype 3; C031000:benzimidazole; D009853:Omeprazole; C009554:fluoroform