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Abingdon, United Kingdom

Horne G.,Summit PLC
Topics in Medicinal Chemistry | Year: 2014

Iminosugars, carbohydrate mimetics in which the endocyclic oxygen of the parent carbohydrate is replaced with nitrogen, are the most important class of carbohydrate mimetic reported to date with two marketed drugs and several in clinical development. Since their first isolation in the 1960s iminosugars have captured the imagination of both synthetic and medicinal chemists alike with recent therapeutic developments highlighting the need for improved routes of synthesis. The resurgence in the therapeutic application of iminosugars has arisen as a consequence of our growing understanding on the role that glycobiology plays in disease and development. There are myriad possible individual targets encompassing a range of therapeutic areas, all of which can potentially be addressed by iminosugars. This chapter presents the historcial development of this compound class before discussing some of the issues that iminosugars present as synthetic targets. The therapeutic potential of this class of compound with specific reference to the development of modulators of glucocerebrosidase activity is discussed. © Springer-Verlag Berlin Heidelberg 2014.

Sattar A.,Evotec | Thommes P.,Evotec | Payne L.,Evotec | Warn P.,Evotec | Vickers R.J.,Summit PLC
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: SMT19969 is a novel narrow-spectrum antimicrobial under development for the treatment of Clostridium difficile infection (CDI). The objectives were to assess the relative efficacies of SMT19969, vancomycin and fidaxomicin in the hamster model of CDI. Methods: Hamsters were infected with either C. difficile BI1 (ribotype 027) or C. difficile 630 (ribotype 012) prior to treatment with vehicle, SMT19969, fidaxomicin or vancomycin for 5 days. Animals were further monitored through to day 28 and survival recorded. Plasma and gastrointestinal concentrations of SMT19969 following single and repeat administration in infected hamsters were determined. Results: Following infection with C. difficile BI1, treatmentwith SMT19969, vancomycin and fidaxomicin resulted in 100% survival during the 5 day dosing period, with 90%-100% of animals receiving SMT19969 and fidaxomicin surviving during the post-dosing follow-up period. Whilst protective during treatment, onset of mortality was observed on day 11 in animals treated with vancomycin, with a 10% survival recorded by day 28. Similar results were observed for SMT19969 and vancomycin following infection with C. difficile 630, with day 28 survival rates of 80%-100%and 0%, respectively. Fidaxomicin protected animals infectedwith C. difficile 630 frommortality during dosing, although day 28 survival rates varied from0%to 40%depending on dose. Plasmalevels of SMT19969were typically below the limit of quantification, but levels in the gastrointestinal tract remained far in excess of the MIC. Conclusions: These data show that SMT19969 is highly effective at treating both acute infection and preventing recurrent disease and support continued investigation of SMT19969 as a potential therapy for CDI. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Baines S.D.,University of Hertfordshire | Crowther G.S.,University of Leeds | Freeman J.,Leeds Teaching Hospitals NHS Trust | Todhunter S.,University of Leeds | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015

Objectives: We investigated the efficacy of the novel antimicrobial agent SMT19969 in treating simulated Clostridium difficile infection using an in vitro human gut model. Methods: Concentrations of the predominant cultivable members of the indigenous gut microfloras and C. difficile (total and spore counts) were determined by viable counting. Cytotoxin titres were determined using cell cytotoxicity and expressed as log10 relative units (RU). Clindamycin was used to induce simulated C. difficile PCR ribotype 027 infection. Once high-level cytotoxin titres (≥4 RU) were observed, SMT19969 was instilled for 7 days. Two SMT19969 dosing regimens (31.25 and 62.5 mg/L four times daily) were evaluated simultaneously in separate experiments. MICs of SMT19969 were determined against 30 genotypically distinct C. difficile ribotypes. Results: SMT19969 was 7- and 17-fold more active against C. difficile than metronidazole and vancomycin, respectively, against a panel of genotypically distinct isolates (P<0.05). Both SMT19969 dosing regimens demonstrated little antimicrobial activity against indigenous gut microflora groups except clostridia. SMT19969 inhibited C. difficile growth and repressed C. difficile cytotoxin titres in the gut model. Conclusions: These data suggest that SMT19969 is a narrow-spectrum and potent antimicrobial agent against C. difficile. Additional studies evaluating SMT19969 in other models of C. difficile infection are warranted, with human studies to place these gut model observations in context. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Weiss W.,University of North Texas Health Science Center | Pulse M.,University of North Texas Health Science Center | Vickers R.,Summit PLC
Antimicrobial Agents and Chemotherapy | Year: 2014

SMT19969 [2,2 ' -bis(4-pyridyl)3H,3'-H 5,5-bibenzimidazole] is a novel narrow-spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficile infection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficile were studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitro activity, with MICs of 0.25 (μg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at 0.5 to 1 μg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 μg/ml to 172 μg/ml). Copyright © 2014 Weiss et al. This is an open access article distributed under the terms of the Creative Commons Attribtion 30 Unported license.

Sloane D.A.,Yorkshire Cancer Research | Trikic M.Z.,Yorkshire Cancer Research | Chu M.L.H.,Stanford University | Lamers M.B.A.C.,Chesterford Research Park | And 5 more authors.
ACS Chemical Biology | Year: 2010

The Aurora kinases regulate multiple aspects of mitotic progression, and their overexpression in diverse tumor types makes them appealing oncology targets. An intensive research effort over the past decade has led to the discovery of chemically distinct families of small molecule Aurora kinase inhibitors, many of which have demonstrated therapeutic potential in model systems. These agents are also important tools to help dissect signaling pathways that are orchestrated by Aurora kinases, and the antiproliferative target of pan-Aurora inhibitors such as VX-680 has been validated using chemical genetic techniques. In many cases the nonspecific nature of Aurora inhibitors toward unrelated kinases is well established, potentially broadening the spectrum of cancers to which these compounds might be applied. However, unambiguously demonstrating the molecular target(s) for clinical kinase inhibitors is an important challenge, one that is absolutely critical for deciphering the molecular basis of compound specificity, resistance, and efficacy. In this paper, we have investigated amino acid requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor MLN8054 and the close analogue MLN8237, a second-generation compound that is in phase II clinical trials. A crystallographic analysis facilitated the design and biochemical investigation of a panel of resistant Aurora A mutants, a subset of which were then selected as candidate drug-resistance targets for further evaluation. Using inducible human cell lines, we show that cells expressing near-physiological levels of a functional but partially drug-resistant Aurora A T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora A as a critical antiproliferative target of these compounds. © 2010 American Chemical Society.

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