Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core

  • ACS Med Chem Lett. 2011 Nov 23;3(1):74-8. doi: 10.1021/ml200252b.
Paul E Harrington  1 ,  Michael D Croghan  1 ,  Christopher Fotsch  1 ,  Mike Frohn  1 ,  Brian A Lanman  1 ,  Lewis D Pennington  1 ,  Alexander J Pickrell  1 ,  Anthony B Reed  1 ,  Kelvin K C Sham  1 ,  Andrew Tasker  1 ,  Heather A Arnett  1 ,  Michael Fiorino  1 ,  Matthew R Lee  1 ,  Michele McElvain  1 ,  Henry G Morrison  1 ,  Han Xu  1 ,  Yang Xu  1 ,  Xuxia Zhang  1 ,  Min Wong  1 ,  Victor J Cee  1
Affiliations
  • 1. Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
PMID: 24900374 DOI: 10.1021/ml200252b
Abstract

The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.

Keywords
S1P1; Sphingosine-1-phosphate receptor; agonist; multiple sclerosis.
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