Tim Hugo Maria Jonckers
Janssen Pharmaceutica
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Publication
Featured researches published by Tim Hugo Maria Jonckers.
Nature Chemical Biology | 2016
Michael Battles; Johannes P. M. Langedijk; Polina Furmanova-Hollenstein; Supranee Chaiwatpongsakorn; Heather M. Costello; Leen Kwanten; Luc Vranckx; Paul Vink; Steffen Jaensch; Tim Hugo Maria Jonckers; Anil Koul; Eric Arnoult; Mark E. Peeples; Dirk Roymans; Jason S. McLellan
Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2012
Tim Hugo Maria Jonckers; Marie-Claude Rouan; Geerwin Yvonne Paul Haché; Wim Schepens; Sabine Hallenberger; Judith Eva Baumeister; Jennifer C. Sasaki
A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent boosting properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.
Journal of Hepatology | 2010
Oliver Lenz; Jan Martin Berke; H. de Kock; P. Van Remoortere; Origène Nyanguile; Sandrine Marie Helene Vendeville; Tim Hugo Maria Jonckers; Pierre Raboisson; Kenny Simmen; Gregory Fanning; Tse-I Lin
Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.
Bioorganic & Medicinal Chemistry Letters | 2018
Serge Maria Aloysius Pieters; David McGowan; Florence Herschke; Frederik Pauwels; Bart Stoops; Werner Constant Johan Embrechts; Annick Scholliers; Wendy Mostmans; Kris Van Dijck; Bertrand Van Schoubroeck; Tine Thoné; Dorien De Pooter; Gregory Fanning; Mari Luz Rosauro; Mourad Daoubi Khamlichi; Ioannis N. Houpis; Eric Arnoult; Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson
The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.
Journal of Medicinal Chemistry | 2018
Werner Constant Johan Embrechts; Florence Herschke; Frederik Pauwels; Bart Stoops; Serge Maria Aloysius Pieters; Vineet Pande; Geert M. E. Pille; Katie Amssoms; Ilham Smyej; Deborah Dhuyvetter; Annick Scholliers; Wendy Mostmans; Kris Van Dijck; Bertrand Van Schoubroeck; Tine Thoné; Dorien De Pooter; Gregory Fanning; Tim Hugo Maria Jonckers; Helen Horton; Pierre Jean-Marie Bernard Raboisson; David McGowan
A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).
Bioorganic & Medicinal Chemistry Letters | 2018
David McGowan; Florence Herschke; Mourad Daoubi Khamlichi; Mari Luz Rosauro; Sara M. Pérez Benedicto; Frederik Pauwels; Bart Stoops; Vineet Pande; Annick Scholliers; Bertrand Van Schoubroeck; Wendy Mostmans; Kris Van Dijck; Tine Thoné; Helen Horton; Gregory Fanning; Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson
In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.
The Practice of Medicinal Chemistry (Fourth Edition) | 2015
Tim Hugo Maria Jonckers
Multitarget drugs are a family of compounds that are designed—either deliberately or by accident—to have a nonselective profile toward biological targets. Totally novel treatment options have emerged from this approach, and in some cases it has brought relief to millions of people in global regions that have suboptimal access to proper medicines. Repositioning of existing drugs for novel indications is therefore considered a valid and welcome strategy that has found support from governmental and nonprofit organizations with the aim of positively impacting the lives of patients in need.
Archive | 2010
Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson; Koen Vandyck; Michael Pelcman; Bengt Christian Sund; Horst Jurgen Wahling; Pedro Pinho; Anna Winqvist; Karl Magnus Nilsson
Archive | 2011
Ludwig Paul Cooymans; Samuël Dominique Demin; Lili Hu; Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson; Abdellah Tahri; Sandrine Marie Helene Vendeville
Archive | 2013
Ioannis N. Houpis; Tim Hugo Maria Jonckers; Pierre Jean-Marie Bernard Raboisson; Abdellah Tahri