2. Academic Validation
  3. Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core

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

Affiliation

  • 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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