Identification of clinical candidates from the benzazepine class of histamine H₃ receptor antagonists

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• 作者：David M. Wilson ; James Apps ; Nicholas Bailey ; Mark J. Bamford ; Isabel J. Beresford ; Kim Brackenborough ; Michael A. Briggs ; Stephen Brough ; Andrew R. Calver ; Barry Crook ; Rebecca K. Davis ; Robert P. Davis ; Susannah Davis ; David K. Dean ; Leanne Harris ; Teresa Heslop ; Vicky Holl ; Phillip Jeffrey ; Terrance A. Panchal ; Christopher A. Parr ; et al.
• 关键词：H3 receptor ; Histamine ; GPCR ; Clinical candidate ; Receptor antagonists ; Neurotransmitters ; Lead optimisation
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 December, 2013
• 年：2013
• 卷：23
• 期：24
• 页码：6890-6896
• 全文大小：3241 K

文摘

This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H₃ receptor antagonists as novel therapies for the treatment of Alzheimer鈥檚 disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H₃ antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.