4-acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a novel class of non-brain-penetrant histamine H3 receptor antagonists
| Autor: | Gemma Victoria White, Helen E. Connor, Elizabeth Pickup, David Matthew Wilson, Clarissa J. Watts, Christopher Browning, Sanjeet Singh Sehmi, Karen M. L. Morriss, Mark James Bamford, Christopher A. Parr, Susannah Davies, Brian Edgar Looker, Panayiotis A. Procopiou, Simon Teanby Hodgson, Fogden Yvonne C, Rachael A. Ancliff, Woodrow Michael David, Duncan S. Holmes |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
ERG1 Potassium Channel Stereochemistry Guinea Pigs Administration Oral CHO Cells In Vitro Techniques Chemical synthesis Piperazines Rats Sprague-Dawley chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Cricetulus Dogs Cytochrome P-450 Enzyme System Ileum Cricetinae Isometric Contraction Drug Discovery Animals Humans Receptor Cerebral Cortex Chemistry Brain Muscle Smooth Penetration (firestop) Ether-A-Go-Go Potassium Channels Bioavailability Rats Isoenzymes Blood-Brain Barrier Molecular Medicine Amine gas treating Histamine H3 receptor Selectivity Histamine Histamine H3 Antagonists |
| Zdroj: | Journal of medicinal chemistry. 50(26) |
| ISSN: | 0022-2623 |
| Popis: | A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|