title: Discovery of the first nonpeptidic, small-molecule, highly selective somatostatin receptor subtype 5 antagonists: a chemogenomics approach.
abstract: We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopamine, and serotonine receptors were identified as the closest neighbors of SST5R. The H1 antagonist astemizole was chosen as a seed structure and subsequently transformed into a SST5 receptor antagonist with nanomolar binding affinity devoid of the original target activity.
authors.affiliation: Discovery Chemistry, Lead Generation, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
authors.forename: Rainer E
authors.initials: RE
authors.lastname: Martin
authors.forename: Luke G
authors.initials: LG
authors.lastname: Green
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Nicole
authors.initials: N
authors.lastname: Kratochwil
authors.forename: Andreas
authors.initials: A
authors.lastname: Christ
mesh_terms: D000595:Amino Acid Sequence; D016589:Astemizole / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D006634:Histamine H1 Antagonists; D010880:Piperidines; D017481:Receptors, Somatostatin; D016589:Astemizole; C094573:somatostatin receptor 5