Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor

Daniel W. Kung, Steven B. Coffey, Ryan M. Jones, Shawn Cabral, Wenhua Jiao, Michael Fichtner, Philip A. Carpino, Colin R. Rose, Richard F. Hank, Michael G. Lopaze, Roger Swartz, Hou Tommy Chen, Zachary Hendsch, Bruce Posner, Christopher F. Wielis, Brian Manning, Jeffrey Dubins, Ingrid A. Stock, Sam Varma, Mary CampbellDemetria Debartola, Rachel Kosa-Maines, Stefanus J. Steyn, Kim F. McClure

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in log P and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

Original languageEnglish (US)
Pages (from-to)4281-4287
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2012

Keywords

  • Antagonist
  • GHS-R1a
  • Ghrelin
  • Inverse agonist
  • Piperidine-azetidine
  • Spirocyclic

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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