4-Acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a Novel Class of Non-Brain-Penetrant Histamine H3 Receptor Antagonists
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- 作者：Panayiotis A. Procopiou ; Rachael A. Ancliff ; Mark J. Bamford ; Christopher Browning ; Helen Connor ; Susannah Davies ; Yvonne C. Fogden ; Simon T. Hodgson ; Duncan S. Holmes ; Brian E. Looker ; Karen M. L. Mo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：December 27, 2007
- 年：2007
- 卷：50
- 期：26
- 页码：6706 - 6717
- 全文大小：184K
- 年卷期：v.50,no.26(December 27, 2007)
- ISSN：1520-4804
文摘
A series of ketopiperazines were prepared and evaluated for their activity as histamine H3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2(R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug−drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.