Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor
- 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
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 July, 2012
- 卷：22
- 期：13
- 页码：4281-4287
- 文件大小：629 K
摘要
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.