Tim Hugo Maria Jonckers

Molecular mechanism of respiratory syncytial virus fusion inhibitors.

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.

Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors.

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.

759 COMBINATION OF TMC435 WITH TWO NOVEL NS5B INHIBITORS INCREASES ANTI HCV ACTIVITY AND RESULTS IN A HIGHER GENETIC BARRIER IN VITRO

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.

Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists

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.

2,4-Diaminoquinazolines as Dual Toll Like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus

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).

Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists

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.

Selective Optimization of Side Activities (SOSA) in Drug Discovery

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.