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

被引：36

作者：

Biggadike, Keith ^{[1
]}

Ahmed, Mahbub ^{[1
]}

Ball, Doug I. ^{[1
]}

Coe, Diane M. ^{[1
]}

Wilk, Deidre A. Dalmas ^{[3
]}

Edwards, Chris D. ^{[1
]}

Gibbon, Bob H. ^{[2
]}

Hardy, Charlotte J. ^{[1
]}

Hermitage, Stephen A. ^{[1
]}

Hessey, Joanne . ^{[1
]}

Hillegas, Aimee E. ^{[3
]}

Hughes, Stephen C. ^{[2
]}

Lazarides, Linos ^{[1
]}

Lewell, Xiao Q. ^{[1
]}

Lucas, Amanda ^{[1
]}

Mallett, David N. ^{[1
]}

Price, Mark A. ^{[2
]}

Priest, Fiona M. ^{[1
]}

Quint, Diana J. ^{[1
]}

Shah, Poonam ^{[1
]}

Sitaram, Anesh ^{[2
]}

Smith, Stephen A. ^{[1
]}

Stocker, Richard ^{[1
]}

Trivedi, Naimisha A. ^{[1
]}

Tsitoura, Daphne C. ^{[1
]}

Weller, Victoria ^{[1
]}

机构：

[1] GlaxoSmithKline R&D, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline R&D, David Jack Ctr, Pk Rd, Ware SG12 0DP, Herts, England

[3] GlaxoSmithKline R&D, 709 Swedeland Rd, King Of Prussia, PA 19406 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 05期

关键词：

IMMUNE-RESPONSE; 8-OXOADENINE DERIVATIVES; BIOLOGICAL EVALUATION; ALLERGIC RHINITIS; INNATE IMMUNITY; TLR7; INTERFERON; STIMULATION; TOLL-LIKE-RECEPTOR-7; 8-HYDROXYADENINES;

D O I：

10.1021/acs.jmedchem.5b01647

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Induction of IFN alpha 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 IFN alpha 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.

引用

页码：1711 / 1726

页数：16

共 60 条

[1] A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma [J].

Aryan, Zahra ;

Holgate, Stephen T. ;

Radzioch, Danuta ;

Rezaei, Nima .

INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY, 2014, 164 (01) :46-63

[2] Accessing the therapeutic potential of immunostimulatory nucleic acids [J].

Barchet, Winfried ;

Wimmenauer, Vera ;

Schlee, Martin ;

Hartmann, Gunther .

CURRENT OPINION IN IMMUNOLOGY, 2008, 20 (04) :389-395

[3] Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives [J].

Bazin, Helene G. ;

Li, Yufeng ;

Khalaf, Juhienah K. ;

Mwakwari, Sandra ;

Livesay, Mark T. ;

Evans, Jay T. ;

Johnson, David A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (06) :1318-1323

[4] Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity [J].

Biffen, M. ;

Matsui, H. ;

Edwards, S. ;

Leishman, A. J. ;

Eiho, K. ;

Holness, E. ;

Satterthwaite, G. ;

Doyle, I. ;

Wada, H. ;

Fraser, N. J. ;

Hawkins, S. L. ;

Aoki, M. ;

Tomizawa, H. ;

Benjamin, A. D. ;

Takaku, H. ;

McInally, T. ;

Murray, C. M. .

BRITISH JOURNAL OF PHARMACOLOGY, 2012, 166 (02) :573-586

[5]

Biggadike K., 2010, Purine Derivatives for the Use in the Treatment of Allergic, Inflammatory and Infectious Diseases, Patent No. [PCT W02010/018133, 2010018133]

[6] Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells [J].

Blasius, Amanda L. ;

Arnold, Carrie N. ;

Georgel, Philippe ;

Rutschmann, Sophie ;

Xia, Yu ;

Lin, Pei ;

Ross, Charles ;

Li, Xiaohong ;

Smart, Nora G. ;

Beutler, Bruce .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (46) :19973-19978

[7] Targeting TNF-α:: A novel therapeutic approach for asthma [J].

Brightling, Christopher ;

Berry, Mike ;

Amrani, Yassine .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2008, 121 (01) :5-10

[8] Recent Developments in United Airways Disease [J].

Ciprandi, Giorgio ;

Caimmi, Davide ;

del Giudice, Michele Miraglia ;

La Rosa, Mario ;

Salpietro, Carmelo ;

Marseglia, Gian Luigi .

ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, 2012, 4 (04) :171-177

[9] Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis [J].

Creticos, Peter S. ;

Schroeder, John T. ;

Hamilton, Robert G. ;

Balcer-Whaley, Susan L. ;

Khattignavong, Arouna P. ;

Lindblad, Robert ;

Li, Henry ;

Coffman, Robert ;

Seyfert, Vicki ;

Eiden, Joseph J. ;

Broide, David .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (14) :1445-1455

[10] Epidemiology of Asthma: Prevalence and Burden of Disease [J].

Croisant, Sharon .

HETEROGENEITY IN ASTHMA, 2014, 795 :17-29

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