Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects
详细信息 查看全文
- 作者：Christian Harcken ; Doris Riether ; Daniel Kuzmich ; Pingrong Liu ; Raj Betageri ; Mark Ralph ; Michel Emmanuel ; Jonathan T. Reeves ; Angela Berry ; Donald Souza ; Richard M. Nelson ; Alison Kukulka ; Tazmeen N. Fadra ; Ljiljana Zuvela-Jelaska ; Roger Dinallo ; J枚rg Bentzien ; Gerald H. Nabozny ; David S. Thomson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 27, 2014
- 年：2014
- 卷：57
- 期：4
- 页码：1583-1598
- 全文大小：587K
- 年卷期：v.57,no.4(February 27, 2014)
- ISSN：1520-4804
文摘
Synthesis and structure鈥揳ctivity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain 鈥渄iazaindole鈥?moieties and display different transcriptional regulatory profiles in vitro and are considered 鈥渄issociated鈥?between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.