Quinolinone-based agonists of S1P1: Use of a N-scan SAR strategy to optimize in vitro and in vivo activity
| Autor: | Kelvin K. C. Sham, Lewis D. Pennington, Paul E. Harrington, Matthew R. Lee, Michele McElvain, Xuxia Zhang, Heather A. Arnett, Min Wong, Alexander J. Pickrell, Anthony B. Reed, Henry Morrison, Victor J. Cee, Mike Fiorino, Christopher H. Fotsch, Michael J. Frohn, Yang Xu, Michael Croghan, Han Xu, Brian A. Lanman, Andrew Tasker, Michelle Horner |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
Stereochemistry medicine.drug_class Chemistry Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biochemistry In vitro Pharmacokinetics In vivo Pharmacodynamics Drug Discovery medicine Molecular Medicine Potency Structure–activity relationship Selectivity Molecular Biology Nuclear chemistry |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:527-531 |
| ISSN: | 0960-894X |
| Popis: | We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat. |
| Databáze: | OpenAIRE |
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