Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor
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- 作者：Daniel W. Kung ; daniel.w.kung@pfizer.com ; 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 ; kim.f.mcclure@pfizer.com
- 关键词：Ghrelin ; GHS-R1a ; Antagonist ; Inverse agonist ; Spirocyclic ; Piperidine-azetidine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 July, 2012
- 年：2012
- 卷：22
- 期：13
- 页码：4281-4287
- 全文大小：629 K
文摘
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 ass=""boldFont"">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 ass=""boldFont"">10a, providing support for further optimization of this series of compounds.