Title: DNDI-VL-2098: a nitroimidazooxazole derivative as a potential clinical candidate to treat Visceral Leishmaniasis Author names: Delphine Launaya, Denis Martina, Stéphanie Braillarda, Preeti Vishwakarmab, Suman Guptab, Sunil Purib, Vanessa Yardleyc, Mvenkata Raod, Vikram Ramanathand, H. Krishnappad, Hari Patid, Andrew Thompsone Author affiliations: a
Drugs for Neglected Diseases initiative, Geneva, Switzerland; bCentral Drug Research Institute, Lucknow, India; cLondon School of Hygiene and Tropical Medicine; dAdvinus Therapeutics, Bangalore, India; eAuckland Cancer Society Research Centre, University of Auckland, New Zealand. Abstract text DNDi (Drugs for Neglected Diseases initiative) is a collaborative, patients’ needs-driven, not-for-profit organization whose mission is to develop new drugs for the most neglected tropical diseases, including Visceral Leishmaniasis (VL). To this purpose, our research effort focused on the nitroimidazole chemical class, well known for its antimicrobial activity, and quickly led to the identification of DNDI-VL-2098 as a potential candidate for VL. This compound is indeed likely to fulfill DNDi’s Target Product Profile, such as: a) effectiveness against L. donovani in East Africa and India (including drug resistant strains), b) 95 % clinical efficacy, c) no contraindications, d) oral formulation, e) dosing once a day for a maximum of 10 days, f) cost under $10 per course. DNDI-VL-2098 is a chiral nitroimidazooxazole analog prepared in 8 steps from commercially available materials. Its in vitro activity (IC50) against different strains of Leishmania donovani ranges from 0.3 to 1 µM. In VL in vivo models, DNDI-VL-2098 showed the following efficacies: -
Total cure at 12.5 mg/kg single dose or 3 mg/kg over 5 days in the acute mouse model Total cure at 50 mg/kg over 3 days or 25 mg/kg over 5 days in the chronic hamster model
The oral bioavailability of DNDI-VL-2098 varied from 70 % (rat) to 100 % (mouse, hamster). Its volume of distribution ranged from 2.0 to 2.5 L/kg (about 3-fold the total body water volume) and the mean elimination half-life ranged from 1.2 (hamster) to 6.0 h (dog). DNDI-VL-2098 moderately inhibited the hERG channel (in transfected Chinese Hamster Ovary cells), with an IC50 of 10.5 µM. However, a telemetry study in male Beagle dogs showed no modification of QTc up to the highest dose tested (250 mg/kg). DNDI-VL-2098 was shown to be neither mutagenic nor clastogenic. In mice and rats, after single dose oral administration, the No-Observed-Effect Level (NOEL) was > 2000 mg/kg. According to allometric scaling predictions for human PK, the minimum efficacious dose in human beings (60 kg) is expected to be in the range of 200 to 600 mg, with a once a day oral administration. In conclusion, DNDI-VL-2098 so far shows promising properties to be developed as a clinical candidate for the treatment of visceral leishmaniasis. Title: Towards the identification of a back-up candidate for DNDI-VL-2098 to treat visceral leishmaniasis