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

• Published in: Journal of medicinal chemistry Vol. 59; no. 5; pp. 1711 - 1726
• Main Authors: Biggadike, Keith, Ahmed, Mahbub, Ball, Doug I, Coe, Diane M, Dalmas Wilk, Deidre A, Edwards, Chris D, Gibbon, Bob H, Hardy, Charlotte J, Hermitage, Stephen A, Hessey, Joanne O, Hillegas, Aimee E, Hughes, Stephen C, Lazarides, Linos, Lewell, Xiao Q, Lucas, Amanda, Mallett, David N, Price, Mark A, Priest, Fiona M, Quint, Diana J, Shah, Poonam, Sitaram, Anesh, Smith, Stephen A, Stocker, Richard, Trivedi, Naimisha A, Tsitoura, Daphne C, Weller, Victoria
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.03.2016
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - chemistry; Adenine - pharmacology; Administration, Intranasal; Asthma - drug therapy; Asthma - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Piperidines - administration & dosage; Piperidines - chemistry; Piperidines - pharmacology; Structure-Activity Relationship; Toll-Like Receptor 7 - agonists
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01647

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.