references
LEISHMANIASIS
R&D MODEL & PORTFOLIO
RESEARCH
Leish H2L
(Leishmaniasis Hit to Lead)
PROJECT START: On-going OVERALL OBJECTIVE: Identify new leads series from current
Oxaborole
(previously known as Oxaleish)
PROJECT START: January 2010 OVERALL OBJECTIVE: Select an oxaborole for pre-clinical
ongoing Hit-to-Lead activities by taking advantage of the optimization consortia platform screening of compounds for VL
2015 OBJECTIVE: Progress two new chemical classes into lead
evaluation
2015 OBJECTIVES:
optimization
• Select an oxaborole for pre-clinical evaluation • Complete profiling of lead oxaboroles
Hit to lead is a dynamic phase in the drug discovery cascade in which small molecule hits from high throughput screens are evaluated and undergo limited optimization to identify promising lead compounds. Series from a number of different partners have shown activity against L. donovani; work on these series to bring forward suitable candidates for lead optimization is on-going.
DNDi and Anacor have been working together over the last few years to identify oxaborole compounds, initially for the HAT programme, and this has expanded to include both leishmaniasis and Chagas disease. DNDI-6148 has emerged as a promising lead candidate and by the end of 2015, studies including exploratory toxicology necessary for possible progression to pre-clinical development had been successfully completed. It is anticipated that pre-clinical development of DNDI-6148 will commence following a review meeting in January 2016. Approximately four additional oxaborole compounds continue to be developed behind DNDI-6148 as potential backups in case an insurmountable issue should be identified.
MAIN PARTNERS: Anacor Pharmaceuticals Inc., USA; Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Belgium; London School of Hygiene and Tropical Medicine (LSHTM), UK; Wuxi AppTech, China; Sandexis, UK
Aminopyrazoles
PROJECT START: February 2012 OVERALL OBJECTIVE: Select an aminopyrazole for pre-clinical
A notable success in January 2015 was the successful advancement of the aminopyrazole series from the hit to lead stage into the next lead optimization stage. This early work has recently been published in J. Med. Chem. In addition, the NTD Drug Discovery Booster project commenced in April 2015 working with four pharmaceutical companies: Eisai, Shionogi, Takeda, and Astra Zeneca and has so far conducted hit expansion on six different hits which are being developed for leishmaniasis and Chagas disease. A number of pharmacokinetic and pharmacodynamic studies have been conducted in animal models of VL using existing and experimental drugs to build improved PK/PD models and ameliorate the translation of new drugs from discovery into clinical studies.
MAIN PARTNERS: Epichem, Australia; UNICAMP (University of
evaluation
2015 OBJECTIVE: Identify compounds suitable for pre-clinical
evaluation
Campinas, Brazil); Centre for Drug Candidate Optimization, Monash University, Australia; TCG Lifesciences, India; Sandexis, UK; WuXi AppTech, China; Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Belgium; London School of Hygiene and Tropical Medicine, UK; Griffith University, Australia; GSK, Tres Cantos, Spain; Sanofi, France; Anacor Pharmaceuticals Inc., USA; Merck, USA; AstraZeneca, UK; AbbVie, USA; Pfizer, UK.
