A Phase I, blinded, randomized, single-centre, parallel-group, single-dose, dose-escalation, placebo-controlled study of the safety, tolerability, and pharmacokinetics of DNDI-6148 after oral dosing in healthy male subjects

Start Date04 Feb 2020

Sponsor / Collaborator

Drugs for Neglected Diseases initiative

100 Clinical Results associated with DNDI-6148

100 Translational Medicine associated with DNDI-6148

100 Patents (Medical) associated with DNDI-6148

Literatures (Medical) associated with DNDI-6148

01 Jan 2025·Journal of Chromatography B

Development and validation of ultra-performance liquid chromatography tandem mass spectrometry methods for the quantitative analysis of the antiparasitic drug DNDI-6148 in human plasma and various mouse biomatrices

Article

Author: Rosing, Hilde ; Van Bocxlaer, Katrien ; Dorlo, Thomas P C ; Schouten, Wietse M ; Kratz, Jadel M ; Beijnen, Jos H ; Beijnen, Jos H. ; Huitema, Alwin D R ; Mowbray, Charles E ; Dorlo, Thomas P.C. ; Mowbray, Charles E. ; Huitema, Alwin D.R. ; Kratz, Jadel M. ; Schouten, Wietse M.

DNDI-6148 is a promising new oral drug for the treatment of cutaneous leishmaniasis (CL), a parasitic neglected tropical disease that affects impoverished populations worldwide. Preclinical target site pharmacokinetics (PK) studies are necessary to evaluate the actual exposure to DNDI-6148 of Leishmania parasites in the skin. To facilitate these investigations, we have developed and validated a reversed phase ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method to quantify DNDI-6148 in relevant target site PK samples, adhering to the relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M10 guideline on bioanalytical method validation. Full validation was performed for the surrogate biomatrices human K₂EDTA plasma, enzymatic digestion buffer and skin microdialysate. Partial validation was conducted for mouse K₂EDTA plasma and tissues. The tissue samples, including mouse skin, liver and spleen, were homogenized using a collagenase A-based enzymatic homogenization workflow. This method was found to be 2.9-fold more effective in extracting DNDI-6148 from skin than the commonly used mechanical homogenization. Protein precipitation was subsequently carried out for all biomatrices. A surrogate biomatrix was used for each method and the range was specifically developed for its intended application, resulting in a linear concentration range of 5.00-2000 ng/mL, 2.00-1000 ng/mL, and 3.00-600 ng/mL for human K₂EDTA plasma, enzymatic digestion buffer and microdialysate, respectively. Each biomatrix had intra- and inter-run accuracy and precision within 15 % for all concentration levels. Matrix effects did not affect the determination of DNDI-6148, since the stable isotopically-labelled internal standard for DNDI-6148 effectively compensated for these matrix effects. Total recovery across all methods was between 73.5 % and 81.3 % (CV ≤4.5 %). DNDI-6148 was stable under various conditions in all the tested biomatrices. However, a decrease in its concentration was observed during homogenization, for which the internal standard corrected adequately. The suitability of the method for use in future preclinical research involving DNDI-6148 was demonstrated in a preclinical target site PK study using a CL-infected murine model.

19 Apr 2024·Organic Process Research & Development

Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148

Article

Author: Jin, Li-Mei ; Khairnar, Pankaj V. ; Cook, Daniel W. ; Satam, Vijay ; Gupton, B. Frank ; Robinson, Stephen J. ; Hochstetler, Samuel R. ; Saathoff, John M. ; Pandya, Urvish ; Shanahan, Charles S. ; Donsbach, Kai O.

Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.

08 Jun 2023·Journal of Medicinal Chemistry

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

Article

Author: Kim, Ho Shin ; Hammill, Jared T. ; Yates, Phillip A. ; Landfear, Scott M. ; Shoeran, Gaurav ; Chen, Yizhe ; Ortiz, Diana ; Guy, R. Kiplin ; Rice, Amy L. ; Sanchez, Marco A. ; Fargo, Corinne M. ; Begley, Kristin L. ; Pistel, William ; Kadayat, Tara Man

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

100 Deals associated with DNDI-6148

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Leishmaniasis	Phase 2	France	Drugs for Neglected Diseases initiative	31 Jan 2020
Chagas Disease	Phase 1	Switzerland	Drugs for Neglected Diseases initiative	30 Jan 2022
Leishmaniasis, Cutaneous	Preclinical	United Kingdom	London School of Hygiene & Tropical Medicine	01 Dec 2019

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