Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Nov 23;3(1):74-8.
doi: 10.1021/ml200252b. eCollection 2012 Jan 12.

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

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

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

Paul E Harrington et al. ACS Med Chem Lett. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Agonists of S1P1.
Scheme 1
Scheme 1. Synthesis of 22
Reagents and conditions: (a) 2-Chloropyridin-4-amine, 120 °C. (b) Ph2O, 220 °C. (c) K2CO3, MeI, 7% yield (3 steps). (d) KOH, 89% yield. (e) Compound 28, HBTU, Et3N, 92% yield. (f) Tributyl(vinyl)stannane, Pd[P(tert-Bu)3]2, CsF, 80 °C, 76% yield. (g) OsO4, NaIO4, 97% yield. (h) LiAlH(Otert-Bu)3, 68% yield.
Figure 2
Figure 2
After a single oral dose, 22 reduced blood lymphocyte counts in female Lewis rats 24 h postdose (N = 3/group; bars represent average blood lymphocyte counts ± SE; circles represent average plasma concentration ± SE; *P < 0.05 vs vehicle by ANOVA/Dunnett's multiple comparsion test). Compound was administered in 20% captisol/1% HPMC/1% pluronic F68, pH 2, with MSA.
See this image and copyright information in PMC

References

    1. Hannun Y. A.; Obeid L. M. Principles of bioactive lipid signaling: lessons from sphingolipids. Nat. Rev. Mol. Cell. Biol. 2008, 9, 139–150. - PubMed
    1. Rosen H.; Gonzalez-Cabrera P. J.; Sanna M. G.; Brown S. Sphingosine-1-phosphate receptor signaling. Annu. Rev. Biochem. 2009, 78, 743–768. - PubMed
    1. Spiegel S.; Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol. 2011, 11, 403–415. - PMC - PubMed
    1. Mandala S.; Hajdu R.; Bergstrom J.; Quackenbush E.; Xie J.; Milligan J.; Thornton R.; Shei G.; Card D.; Keohane C.; Rosenbach M.; Hale J.; Lynch C. L.; Rupprecht K.; Parsons W.; Rosen H. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346–349. - PubMed
    1. Brinkmann V.; Davis M. D.; Heise C. E.; Albert R.; Cottens S.; Hof R.; Bruns C.; Prieschl E.; Baumruker T.; Hiestand P.; Foster C. A.; Zollinger M.; Lynch K. R. The immune modulator FTY720 targets sphingosine-1-phosphate receptors. J. Biol. Chem. 2002, 277, 21453–21457. - PubMed

LinkOut - more resources