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Linda Otterson - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel dna gyrase inhibiting spiropyrimidinetriones benzisoxazole fusion with n linked oxazolidinone substituents leading to a clinical candidate etx0914
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Gregory S Basarab, Peter Doig, Vincent Galullo, Gunther Kern, Amy Kimzey, Amy Kutschke, Joseph P. Newman, Marshall Morningstar, John P Mueller, Linda Otterson
    Abstract:

    A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro Toxicity profile, including no genoToxicity and no Bone Marrow Toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes i...

  • Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N‑Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)
    2015
    Co-Authors: Gregory S Basarab, Peter Doig, Vincent Galullo, Gunther Kern, Amy Kimzey, Amy Kutschke, Joseph P. Newman, Marshall Morningstar, John Mueller, Linda Otterson
    Abstract:

    A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro Toxicity profile, including no genoToxicity and no Bone Marrow Toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile

A M T Boerbooms - One of the best experts on this subject based on the ideXlab platform.

  • azathioprine related Bone Marrow Toxicity and low activities of purine enzymes in patients with rheumatoid arthritis
    Arthritis & Rheumatism, 1995
    Co-Authors: P J S M Kerstens, J Stolk, R A De Abreu, L H J Lambooy, L B A Van De Putte, A M T Boerbooms
    Abstract:

    Objective. Azathioprine (AZA) metabolism largely parallels the endogenous purine pathways. To date, thiopurine methyltransferase (TPMT) deficiency has been reported as a cause of AZA-related Bone Marrow Toxicity in 1 patient with rheumatoid arthritis (RA). We therefore studied purine enzyme activities in 3 patients with RA who experienced AZA-related Bone Marrow Toxicity. Methods. Lymphocyte activity of purine nucleoside phosphorylase and 5′-nucleotidase (5NT) and erythrocyte activity of TPMT, key enzymes in thiopurine catabolism, were measured in 3 RA patients who had experienced AZA-related Bone Marrow Toxicity and in 16 RA patients without signs of Toxicity despite at least 6 months of treatment with AZA. Results. Two patients with AZA-related Bone Marrow Toxicity were found to have a TPMT deficiency, 1 partial and 1 total. In the third patient, 5NT activity was found to be well below the lowest level observed in the control subjects. Conclusion. All 3 patients with severe AZA-related Bone Marrow Toxicity had abnormal purine enzyme activities. Deficiency of purine enzymes, including TPMT and 5NT, may be a cause of AZA-related Bone Marrow Toxicity in patients with RA.

H Ulrichts - One of the best experts on this subject based on the ideXlab platform.

  • combination chemotherapy with vindesine ifosfamide cisplatin vip in locally advanced unresectable stage iii and in stage iv non small cell lung cancer a phase ii trial
    Lung Cancer, 1995
    Co-Authors: Johan Vansteenkiste, J Vandebroek, S Marien, L Roex, P Bertrand, J Bockaert, T De Beukelaar, R Deman, P De Muynck, H Ulrichts
    Abstract:

    Abstract The efficacy and Toxicity of a regimen adding ifosfamide to the more classical cisplatin-vindesine combination was studied in patients with advanced non-small cell lung cancer. Sixty-four good performance patients with inoperable stage III or stage IV were treated with VIP: vindesine 3 mg/m 2 days 1 and 8, ifosfamide 1200 mg/m 2 and platinum 30 mg/m 2 days 1, 2 and 3, repeated every 4 weeks, up to a maximum of six cycles. Response rate, clinical data and radiological tests were rigourously reviewed by a panel. Overall response rate was 39% (95% confidence interval, 27%–51%) with three patients achieving a complete response; response rate in stage III was 48%. Median survival was 9 months. Toxicity consisted mainly of Bone Marrow Toxicity and nausea/vomiting, but was manageable. There was no renal Toxicity greater than grade 2, four severe infections, but no treatment-related deaths. Conclusion: VIP as mentioned above is very active in good performance patients with advanced non-small cell lung cancer. Its activity, together with its manageable Toxicity—without severe renal or pulmonary Toxicity—makes it an attractive candidate for induction chemotherapy.

Esther Garciaplanella - One of the best experts on this subject based on the ideXlab platform.

  • new genetic associations in thiopurine related Bone Marrow Toxicity among inflammatory bowel disease patients
    Pharmacogenomics, 2013
    Co-Authors: William Zabala, Raquel Cruz, Manuel Barreirode Acosta, Maria Chaparro, Julian Panes, Ana Echarri, M Esteve, Daniel Carpio, Montserrat Andreu, Esther Garciaplanella
    Abstract:

    Background: The Toxicity related to thiopurine drug therapy for inflammatory bowel disease (IBD) varies widely among patients. Almost 15–30% of patients with IBD develop side effects during treatment, often Bone Marrow suppression. Several factors have been implicated in determining this Toxicity, mainly individual genetic variation related to formation of active thiopurine metabolites. The aim was to identify genes involved in thiopurine-related myelosuppression. Materials & methods: A two-stage investigation of 19,217 coding SNPs (cSNPs) was performed in a Spanish (Inflammatory Bowel Disease Group of Galicia [EIGA]) cohort of 173 IBD patients, 15 with Bone Marrow suppression. The top 20 cSNPs identified in the first stage with p < 10-3 for allelic test association and SNPs that define the common TPMT alleles were replicated in a different Spanish (ENEIDA) cohort (87 patients, 29 with Bone Marrow suppression). Results: Several cSNPs showed a significant p-value in the allelic joint analysis (p-Cochran–Ma...

Gregory S Basarab - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel dna gyrase inhibiting spiropyrimidinetriones benzisoxazole fusion with n linked oxazolidinone substituents leading to a clinical candidate etx0914
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Gregory S Basarab, Peter Doig, Vincent Galullo, Gunther Kern, Amy Kimzey, Amy Kutschke, Joseph P. Newman, Marshall Morningstar, John P Mueller, Linda Otterson
    Abstract:

    A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro Toxicity profile, including no genoToxicity and no Bone Marrow Toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes i...

  • Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N‑Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)
    2015
    Co-Authors: Gregory S Basarab, Peter Doig, Vincent Galullo, Gunther Kern, Amy Kimzey, Amy Kutschke, Joseph P. Newman, Marshall Morningstar, John Mueller, Linda Otterson
    Abstract:

    A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro Toxicity profile, including no genoToxicity and no Bone Marrow Toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile