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 =0.020μM, 120% efficacy; 5: EC 50 =0.070μM, 110% efficacy) and selectivity (hS1P 3 Ca 2+ flux; 17: EC 50 >25μM; 5: EC 50 =1.5μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15L/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 =15h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=−67%; 5: 3mg/kg po, 24h PLC POC=−51%) in rat.