title: Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses.
abstract: FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: James M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Campbell
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Nigel
authors.initials: N
authors.lastname: Deeks
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dowell
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Colin
authors.initials: C
authors.lastname: Eldred
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Pam
authors.initials: P
authors.lastname: Gaskin
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: James R J
authors.initials: JR
authors.lastname: Gray
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haynes
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hirst
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kumar
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Morse
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Osborne
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Renaux
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Gail A L
authors.initials: GA
authors.lastname: Seal
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Smethurst
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Watson
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Willis
authors.affiliation: Immuno Inflammation Therapeutic Area Unit, and ‡Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: C000609011:3-(2-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-3-methyl-6,7-dihydro-2H-pyrazolo(4,3-c)pyridin-5(4H)-yl)propanoic acid; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors