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...

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Veröffentlicht in:	Journal of medicinal chemistry 2007-12, Vol.50 (25), p.6295-6298
Hauptverfasser:	Guba, Wolfgang, Green, Luke G, Martin, Rainer E, Roche, Olivier, Kratochwil, Nicole, Mauser, Harald, Bissantz, Caterina, Christ, Andreas, Stahl, Martin
Format:	Artikel
Sprache:	eng
Schlagworte:	Astemizole - chemistry Astemizole - pharmacology Binding Sites Biological and medical sciences Combinatorial Chemistry Techniques Databases, Factual Histamine H1 Antagonists - chemistry Histamine H1 Antagonists - pharmacology Humans Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Somatostatin - antagonists & inhibitors Receptors, Somatostatin - chemistry Receptors, Somatostatin - genetics Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm701144e