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  • Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

Bioorganic & medicinal chemistry letters (2011-11-23)
Lewis D Pennington, Michael D Croghan, Kelvin K C Sham, Alexander J Pickrell, Paul E Harrington, Michael J Frohn, Brian A Lanman, Anthony B Reed, Matthew R Lee, Han Xu, Michele McElvain, Yang Xu, Xuxia Zhang, Michael Fiorino, Michelle Horner, Henry G Morrison, Heather A Arnett, Christopher Fotsch, Andrew S Tasker, Min Wong, Victor J Cee
PMID22104144
ABSTRACT

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.