Biomedical subjects

Koen Andries

Publications and source records attributed to Koen Andries.

22 records · Page 2Linked to original sources

PubMed2003

3-iodo-4-phenoxypyridinones (IOPY's), a new family of highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Building upon the potent anti-HIV-1 activities observed for the 3-dimethylamino-4-benzylpyridinone 2, and the corresponding 4-aryloxypyridinone analogue 3, a concise and efficient route to the 3-iodo-4-aryloxypyridinones 14a-c (IOPY's) was developed. This involved reaction of the 4-hydroxy substituted pyridinone 10 with the requisite dichloroiodobenzene reagent 11. IOPY compound 14c is active at IC(50)=1-45 nM against wild type HIV-1 and a panel of six major simple/double HIV mutant strains.

HIV-1↗

PubMed2003

Short duration aerosols of JNJ 2408068 (R170591) administered prophylactically or therapeutically protect cotton rats from experimental respiratory syncytial virus infection.

Cotton rats exposed to continuous small droplet aerosols of 2[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]methyl]-6-methyl-3-pyridinol (JNJ 2408068) or its hydrochloric salt for only 15 min, one day prior to virus inoculation or one day after, were significantly protected from pulmonary respiratory syncytial virus (RSV) infection compared to control animals similarly infected but exposed to aerosols of placebo at these times. No evidence of toxicity was seen in any of these animals or in cotton rats administered 10 times the minimum cotton rat efficacious dose (i.e. 10x0.39 mg of active compound per kilogram of body weight) for four continuous days. The marked selective antiviral activity observed in the cotton rats mirrored that seen for these compounds in cytotoxicity and antiviral assays performed against RSV in vitro. Plasma kinetics and tissue distribution of JNJ 2408068 in cotton rats following inhalation were determined in separate experiments performed using conditions similar to those utilized in the in vivo efficacy studies. The data from these experiments indicated that significant levels of the test compound were delivered to the lungs of exposed animals, but that extrapulmonary distribution was limited.

Administration, Inhalation↗

PubMed2003

Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus.

A cell-based assay was used to discover compounds inhibiting respiratory syncytial virus (RSV)-induced fusion in HeLa/M cells. A lead compound was identified and subsequent synthesis of >300 analogues led to the identification of JNJ 2408068 (R170591), a low molecular weight (MW 395) benzimidazole derivative with an EC(50) (0.16 nM) against some lab strains almost 100,000 times better than that of ribavirin (15 microM). Antiviral activity was confirmed for subgroup A and B clinical isolates of human RSV and for a bovine RSV isolate. The compound did not inhibit the growth of representative viruses from other Paramyxovirus genera, i.e. HPIV2 and Mumps Virus (genus Rubulavirus), HPIV3 (genus Respirovirus), Measles virus (genus Morbillivirus) and hMPV. Efficacy in cytopathic effect inhibition assays correlated well with efficacy in virus yield reduction assays. A concentration of 10nM reduced RSV production 1000-fold in multi-cycle experiments, irrespective of the multiplicity of infection. Time of addition studies pointed to a dual mode of action: inhibition of virus-cell fusion early in the infection cycle and inhibition of cell-cell fusion at the end of the replication cycle. Two resistant mutants were raised and shown to have single point mutations in the F-gene (S398L and D486N). JNJ 2408068 was also shown to inhibit the release of proinflammatory cytokines IL-6, IL-8 and Rantes from RSV-infected A549 cells.

Antiviral Agents↗

PubMedDate not supplied

On the detection of multiple-binding modes of ligands to proteins, from biological, structural, and modeling data.

There are several indications that a given compound or a set of related compounds can bind in different modes to a specific binding site of a protein. This is especially evident from X-ray crystallographic structures of ligand-protein complexes. The availability of multiple binding modes of a ligand in a binding site may present an advantage in drug design when simultaneously optimizing several criteria. In the case of the design of anti-HIV compounds we observed that the more active compounds that are also resilient against mutation of the non-nucleoside binding site of HIV1-reverse transcriptase make use of more binding modes than the less active and resilient compounds.

Anti-HIV Agents↗