2. Academic Validation
  3. 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

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):527-31. doi: 10.1016/j.bmcl.2011.10.085.
Lewis D Pennington 1,  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
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. lewpenn@me.com
PMID: 22104144 DOI: 10.1016/j.bmcl.2011.10.085
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.

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