Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: Discovery of (R)-1-(2-(4?(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)
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- 作者：Graeme Semple ; gsemple@arenapharm.com ; Vincent J. Santora ; Jeffrey M. Smith ; Jonathan A. Covel ; Rena Hayashi ; Charlemagne Gallardo ; Jason B. Ibarra ; Jeffrey A. Schultz ; Douglas M. Park ; Scott A. Estrada ; Brian J. Hofilena ; Brian M. Smith ; Albert Ren ; Marissa Suarez ; John Frazer ; Jeffrey E. Edwards ; Ryan Hart ; Erin K. Hauser ; Jodie Lorea ; Andrew J. Grottick
- 关键词：Histamine-H3 antagonist ; Sleep ; Wakefulness ; CNS ; hERG ; Clinical candidate
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 January, 2012
- 年：2012
- 卷：22
- 期：1
- 页码：71-75
- 全文大小：318 K
文摘
The design of a new clinical candidate histamine-H3 receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.