title: From astemizole to a novel hit series of small-molecule somatostatin 5 receptor antagonists via GPCR affinity profiling.
abstract: 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.
authors.affiliation: Discovery Chemistry, Lead Generation, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. wolfgang.guba@roche.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Luke G
authors.initials: LG
authors.lastname: Green
authors.forename: Rainer E
authors.initials: RE
authors.lastname: Martin
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
authors.forename: Nicole
authors.initials: N
authors.lastname: Kratochwil
authors.forename: Harald
authors.initials: H
authors.lastname: Mauser
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Andreas
authors.initials: A
authors.lastname: Christ
authors.forename: Martin
authors.initials: M
authors.lastname: Stahl
mesh_terms: 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
chemical_list: D006634:Histamine H1 Antagonists; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D017481:Receptors, Somatostatin; D013141:Spiro Compounds; D016589:Astemizole; C094573:somatostatin receptor 5