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

Bioorg Med Chem Lett. 2012 Jan 1;22(1):527-31. doi: 10.1016/j.bmcl.2011.10.085. Epub 2011 Nov 4.

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.

MeSH terms

  • Animals
  • Area Under Curve
  • Cardiovascular Diseases / metabolism
  • Chemistry, Physical / methods*
  • Drug Design
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Kinetics
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Models, Chemical
  • Multiple Sclerosis / drug therapy
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / chemistry*
  • Structure-Activity Relationship

Substances

  • Immunosuppressive Agents
  • Quinolones
  • Receptors, Lysosphingolipid