2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Mar 10;59(5):1711-26. doi: 10.1021/acs.jmedchem.5b01647.
Keith Biggadike 1,  Mahbub Ahmed 1,  Doug I Ball 1,  Diane M Coe 1,  Deidre A Dalmas Wilk 2,  Chris D Edwards 1,  Bob H Gibbon 3,  Charlotte J Hardy 1,  Stephen A Hermitage 1,  Joanne O Hessey 1,  Aimee E Hillegas 2,  Stephen C Hughes 3,  Linos Lazarides 1,  Xiao Q Lewell 1,  Amanda Lucas 1,  David N Mallett 1,  Mark A Price 3,  Fiona M Priest 1,  Diana J Quint 1,  Poonam Shah 1,  Anesh Sitaram 3,  Stephen A Smith 1,  Richard Stocker 1,  Naimisha A Trivedi 1,  Daphne C Tsitoura 1,  Victoria Weller 1
Affiliations

Affiliations

  • 1 GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 GlaxoSmithKline R&D, UpperMerion , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
  • 3 GlaxoSmithKline R&D, David Jack Centre , Park Road, Ware, Hertfordshire SG12 ODP, U.K.
PMID: 26861551 DOI: 10.1021/acs.jmedchem.5b01647
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.

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