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. 2011 Mar 24;2(6):444-9.
doi: 10.1021/ml2000214. eCollection 2011 Jun 9.

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

Emmanuel H Demont  1 , Benjamin I Andrews  1 , Rino A Bit  1 , Colin A Campbell  1 , Jason W B Cooke  1 , Nigel Deeks  1 , Sapna Desai  1 , Simon J Dowell  1 , Pam Gaskin  1 , James R J Gray  1 , Andrea Haynes  1 , Duncan S Holmes  1 , Umesh Kumar  1 , Mary A Morse  1 , Greg J Osborne  1 , Terry Panchal  1 , Bela Patel  1 , Alcide Perboni  1 , Simon Taylor  1 , Robert Watson  1 , Jason Witherington  1 , Robert Willis  1
Affiliations

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

Emmanuel H Demont et al. ACS Med Chem Lett. .

Abstract

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

Keywords: Fingolimod; S1P; agonism; bradycardia; lymphopenia; multiple sclerosis.

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Figures

Figure 1
Figure 1
Structures of fingolimod 1 and its phosphate 3, myriocin 2, and S1P 4.
Figure 2
Figure 2
Structures of known S1P1 agonists.
Figure 3
Figure 3
Structure of biaryl oxadiazoles.
Scheme 1
Scheme 1. Lead Generation Strategy Toward Druglike S1P1 Agonist Leads
Reagents and conditions: (a) Palladium-mediated nitrile formation. (b) Addition of hydroxylamine. (c) Compound 11, base, heat. (d) HCl. (e) Alkylation. (f) Saponification.
Scheme 2
Scheme 2. Synthesis of 20
Reagents and conditions: (a) Pyrrolidine, toluene, Dean−Stark, reflux. (b) Pent-1-en-3-one, hydroquinone, 59% (2 steps). (c) Lithium bis(trimethylsilyl)amide (LiHMDS), THF, −63 °C and then trimethylsilyl chloride (TMSCl). (d) Pd(OAc)2, CH3CN, T < 35 °C, and then tetra-n-butylammonium fluoride (TBAF), 55% (2 steps). (e) Tf2O, pyridine, CH2Cl2, −30 °C. (f) Zn(CN)2, Pd(PPh3)4, DMF, 100 °C, 92% (2 steps). (g) Aqueous NH2OH, EtOH, 80 °C, 86%. (h) Compound 15, pyridine, toluene, 0−110 °C, 51% (2 steps). (i) HCl, dioxane, room temperature, 98%. (j) Ethyl acrylate, diaza(1,3)bicycle[5.4.0]undecane (DBU), CH3CN, room temperature, 94%. (k) NaOH, EtOH/water, room temperature, 91%.
Figure 4
Figure 4
Lymphocyte reduction over time following oral administration of 20 (as sodium salt) in rats.
Figure 5
Figure 5
Effect of once daily dosing of 20 (as free base) on paw volume in rat collagen-induced arthritis model. *p < 0.05, **<0.01, and ***<0.001 vs arthritic control ANOVA, posthoc LS means.
Figure 6
Figure 6
Comparison of the effect of 20 (sodium salt) and 1 on heart rate over time in rats following oral administration.
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