Development of DNDI-0690: A new clinical candidate for visceral leishmaniasis

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Show simple item record Thompson, Andrew en O'Connor, PD en Marshall, AJ en Yardley, V en Maes, L en Launay, D en Chatelain, E en Denny, William en
dc.coverage.spatial Lucknow, India en 2019-10-21T00:13:53Z en 2019-02-21 en
dc.identifier.citation 7th International Symposium on Current Trends in Drug Discovery Research, 21 Feb 2019 en
dc.identifier.uri en
dc.description.abstract Visceral leishmaniasis (VL) is a fatal sandfly-borne disease that is caused by the parasites Leishmania donovani (Indian subcontinent, Eastern Africa) and Leishmania infantum (Latin America, Central Asia, and Mediterranean region). The few available treatment options for VL all suffer from various drawbacks and there is an urgent need for affordable, short-course oral drugs with enhanced safety and efficacy (especially in Eastern Africa). Bicyclic nitroimidazole derivatives were initially explored by us, as part of an anti-tuberculosis drug development program with the TB Alliance. Phenotypic screening of selected early examples by DNDi and follow-up in vivo assessment led to the rapid identification of nitroimidazooxazole 1 as a preclinical candidate for VL. A collaborative backup project between Auckland University and DNDi was then launched to investigate two related nitroimidazooxazine classes derived from the drug pretomanid (2). More than 330 new analogues were prepared, including over 100 in the promising 7-substituted class, seeking to optimally balance physicochemical and pharmacokinetic properties, efficacy, and safety. When 1 failed to meet all of the criteria for clinical evaluation, two excellent backup candidates (DNDI-8219, 3 and DNDI-0690, 4) were assessed in a 14 day rat toxicity study, and the latter was selected for advanced development. Structure-activity relationships and several new results will be presented. en
dc.relation.ispartof 7th International Symposium on Current Trends in Drug Discovery Research en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title Development of DNDI-0690: A new clinical candidate for visceral leishmaniasis en
dc.type Presentation en
dc.rights.holder Copyright: The authors en
pubs.finish-date 2019-02-23 en
pubs.start-date 2019-02-20 en
dc.rights.accessrights en
pubs.subtype Conference Oral Presentation en
pubs.subtype Invited en
pubs.elements-id 783356 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2019-10-02 en

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