title: Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma.
abstract: Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Keith
authors: K
authors: Biggadike
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Mahbub
authors: M
authors: Ahmed
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Doug I
authors: DI
authors: Ball
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Diane M
authors: DM
authors: Coe
authors: GlaxoSmithKline R&D, UpperMerion , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors: Deidre A
authors: DA
authors: Dalmas Wilk
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Chris D
authors: CD
authors: Edwards
authors: GlaxoSmithKline R&D, David Jack Centre , Park Road, Ware, Hertfordshire SG12 ODP, U.K.
authors: Bob H
authors: BH
authors: Gibbon
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Charlotte J
authors: CJ
authors: Hardy
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Stephen A
authors: SA
authors: Hermitage
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Joanne O
authors: JO
authors: Hessey
authors: GlaxoSmithKline R&D, UpperMerion , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors: Aimee E
authors: AE
authors: Hillegas
authors: GlaxoSmithKline R&D, David Jack Centre , Park Road, Ware, Hertfordshire SG12 ODP, U.K.
authors: Stephen C
authors: SC
authors: Hughes
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Linos
authors: L
authors: Lazarides
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Xiao Q
authors: XQ
authors: Lewell
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Amanda
authors: A
authors: Lucas
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: David N
authors: DN
authors: Mallett
authors: GlaxoSmithKline R&D, David Jack Centre , Park Road, Ware, Hertfordshire SG12 ODP, U.K.
authors: Mark A
authors: MA
authors: Price
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Fiona M
authors: FM
authors: Priest
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Diana J
authors: DJ
authors: Quint
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Poonam
authors: P
authors: Shah
authors: GlaxoSmithKline R&D, David Jack Centre , Park Road, Ware, Hertfordshire SG12 ODP, U.K.
authors: Anesh
authors: A
authors: Sitaram
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Stephen A
authors: SA
authors: Smith
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Richard
authors: R
authors: Stocker
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Naimisha A
authors: NA
authors: Trivedi
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Daphne C
authors: DC
authors: Tsitoura
authors: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Victoria
authors: V
authors: Weller
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000281:Administration, Intranasal; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: C000603511:GSK2245035; D010880:Piperidines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D000225:Adenine