From astemizole to a novel hit series of small-molecule somatostatin 5 receptor antagonists via GPCR affinity profiling.
The H1R antagonist astemizole was identified as a somatostatin 5 (SST5) receptor antagonist by a comparative sequence analysis of the consensus drug binding pocket of GPCRs. Subsequently, a similarity analysis of GPCR affinity profiles of astemizole versus a set of in-house GPCR-biased combinatorial libraries revealed new chemical entry points that led to a second lead series with nanomolar binding affinity.
Guba
Wolfgang
W
Discovery Chemistry, Lead Generation, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. wolfgang.guba@roche.com
Green
Luke G
LG
Martin
Rainer E
RE
Roche
Olivier
O
Kratochwil
Nicole
N
Mauser
Harald
H
Bissantz
Caterina
C
Christ
Andreas
A
Stahl
Martin
M
D016589:Astemizole / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006634:Histamine H1 Antagonists; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D017481:Receptors, Somatostatin; D013141:Spiro Compounds; D016589:Astemizole; C094573:somatostatin receptor 5