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

开始日期2020-02-04

申办/合作机构

Drugs for Neglected Diseases initiative

100 项与 DNDI-6148 相关的临床结果

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100 项与 DNDI-6148 相关的转化医学

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100 项与 DNDI-6148 相关的专利（医药）

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项与 DNDI-6148 相关的文献（医药）

2024-04-19·Organic Process Research & Development

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

Article

作者: Jin, Li-Mei ; Khairnar, Pankaj V. ; Cook, Daniel W. ; Gupton, B. Frank ; Satam, Vijay ; 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.

2021-11-11·Journal of Medicinal Chemistry1区 · 医学

DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis

1区 · 医学

Article

作者: Wyllie, Susan ; Corpas-Lopez, Victoriano ; Glossop, Paul A. ; Zuccotto, Fabio ; Van den Kerkhof, Magali ; Braillard, Stéphanie ; Jacobs, Robert T. ; Pandi, Bharathi ; Patterson, Stephen ; Yardley, Vanessa ; Freund, Yvonne ; Lukac, Iva ; Gilbert, Ian H. ; Whitlock, Gavin A. ; Speake, Jason ; Wall, Richard J. ; Carvalho, Sandra ; Bello, Davide ; Maes, Louis ; Mowbray, Charles E. ; Caljon, Guy ; Nare, Bakela

Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.

2019-12-01·International Journal for Parasitology: Drugs and Drug Resistance2区 · 医学

Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis

2区 · 医学

ArticleOA

作者: Vesely, Brian ; Sciotti, Richard J ; Ioset, Jean-Robert ; Leed, Susan ; Mowbray, Charles E ; Braillard, Stéphanie ; Caridha, Diana ; Wijnant, Gert-Jan ; Croft, Simon L ; Van Bocxlaer, Katrien ; Black, Chad ; Yardley, Vanessa

OBJECTIVESDrugs for Neglected Diseases initiative (DNDi) has identified three chemical lead series, the nitroimidazoles, benzoxaboroles and aminopyrazoles, as innovative treatments for visceral leishmaniasis. The leads discovered using phenotypic screening, were optimised following disease- and compound-specific criteria. Several leads of each series were progressed and preclinical drug candidates have been nominated. Here we evaluate the efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis.METHODSThe in vitro activity of fifty-five compounds was evaluated against the intracellular amastigotes of L. major, L. aethiopica, L. amazonensis, L. panamensis, L. mexicana and L. tropica. The drugs demonstrating potent activity (EC₅₀ < 5 μM) against at least 4 of 6 species were subsequently evaluated in vivo in different L. major - BALB/c mouse models using a 5 or 10-day treatment with either the oral or topical formulations. Efficacy was expressed as lesion size (measured daily using callipers), parasite load (by quantitative PCR - DNA) and bioluminescence signal reduction relative to the untreated controls.RESULTSThe selected drug compounds (3 nitroimidazoles, 1 benzoxaborole and 3 aminopyrazoles) showed consistent and potent activity across a range of Leishmania species that are known to cause CL with EC₅₀ values ranging from 0.29 to 18.3 μM. In all cases, this potent in vitro antileishmanial activity translated into high levels of efficacy with a linear dose-response against murine CL. When administered at 50 mg/kg/day, DNDI-0690 (nitroimidazole), DNDI-1047 (aminopyrazole) and DNDI-6148 (benzoxaborole) all resulted in a significant lesion size reduction (no visible nodule) and an approximate 2-log-fold reduction of the parasite load as measured by qPCR compared to the untreated control.CONCLUSIONSThe lead compounds DNDI-0690, DNDI-1047 and DNDI-6148 showed excellent activity across a range of Leishmania species in vitro and against L. major in mice. These compounds offer novel potential drugs for the treatment of CL.

100 项与 DNDI-6148 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
Chagas病	临床1期	瑞士	Drugs for Neglected Diseases initiative	2022-01-30
利什曼病	临床前	法国	Drugs for Neglected Diseases initiative	2020-01-31