2. Academic Validation
  3. Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor

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

  • Bioorg Med Chem Lett. 2012 Jul 1;22(13):4281-7. doi: 10.1016/j.bmcl.2012.05.024.
Daniel W Kung 1,  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 Campbell,  Demetria DeBartola,  Rachel Kosa-Maines,  Stefanus J Steyn,  Kim F McClure
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA. [email protected]
PMID: 22677316 DOI: 10.1016/j.bmcl.2012.05.024
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 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.

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