Bioorganic & Medicinal Chemistry Letters 2012-07-01

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 Campbell, Demetria DeBartola, Rachel Kosa-Maines, Stefanus J Steyn, Kim F McClure

Index: Bioorg. Med. Chem. Lett. 22(13) , 4281-7, (2012)

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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.Copyright © 2012 Elsevier Ltd. All rights reserved.