title: Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate.
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.
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Andrews
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Campbell
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Jason W B
authors.initials: JW
authors.lastname: Cooke
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Deeks
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Sapna
authors.initials: S
authors.lastname: Desai
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dowell
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Pam
authors.initials: P
authors.lastname: Gaskin
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: James R J
authors.initials: JR
authors.lastname: Gray
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haynes
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kumar
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Morse
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Osborne
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Terry
authors.initials: T
authors.lastname: Panchal
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Bela
authors.initials: B
authors.lastname: Patel
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Alcide
authors.initials: A
authors.lastname: Perboni
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Watson
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Willis
keywords: Fingolimod; S1P; agonism; bradycardia; lymphopenia; multiple sclerosis