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
| Autor: | Victoria Weller, Poonam Shah, David N. Mallett, Mark Price, Joanne O. Hessey, Diane M. Coe, Stephen C. Hughes, Charlotte J. Hardy, Amanda Lucas, Xiao Qing Lewell, Doug Ball, Bob H. Gibbon, Stephen A. Smith, Anesh Sitaram, Linos Lazarides, Keith Biggadike, Daphne Tsitoura, Stephen A. Hermitage, Richard Stocker, Chris D. Edwards, Mahbub Ahmed, Diana Quint, Fiona Priest, Deidre Dalmas Wilk, Aimee Hillegas, Naimisha Trivedi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Pharmacology Compound 32 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Downregulation and upregulation Piperidines In vivo Drug Discovery medicine Structure–activity relationship Potency Humans Administration Intranasal Dose-Response Relationship Drug Molecular Structure Chemistry Adenine TLR7 Asthma 030104 developmental biology Toll-Like Receptor 7 030220 oncology & carcinogenesis Molecular Medicine Nasal administration |
| Zdroj: | Journal of medicinal chemistry. 59(5) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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