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
  • 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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