Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments

Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis.

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.The authors acknowledge funding from the National Institute of Allergy and Infectious Diseases (M.P.P. and M.N., R01AI114685; M.P.P., 1R21AI127594, R01AI124046; C.R.C., R21AI126296; https://www.niaid.nih.gov/), the Spanish Ministerio de Economí a, Industria y Competitividad (M.N., SAF2015-71444-P; D.G.-P., SAF2016-79957-R; http://www.mineco.gob.es), Subdireccion General de Redes ́ y Centros de Investigacion Cooperativa (RICET, https://www.ricet.es/) (M.N., RD16/0027/0019; D.G.P., RD16/ 0027/0014), and RTI2018-097210-B-I00 (MINCIU-FEDER) to F.G. An ACS MEDI Predoctoral Fellowship for D.M.K. is gratefully acknowledged, as is support from the National Science Foundation for K.F. (CHE-1262734). We thank AstraZeneca, Charles River Laboratories, and GlaxoSmithKline for the provision of the in vitro ADME and physicochemical properties data. The use of JChem/ChemAxon software is acknowledged

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice

A diverse view of science to catalyse change

Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions

A diverse view of science to catalyse change:Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. we must value diversity not only in words, but also in actions

No abstract available.publishe

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID

Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis

From a high-throughput screen of 42 444 knownhuman kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold wasidentified to begin optimization for the treatment of human Africantrypanosomiasis. Previously reported data for analogous com-pounds against human kinases GSK-3β, CDK-2, and CDK-4 wereleveraged to try to improve the selectivity of the series, resulting in23awhich showed selectivity forT. b. bruceiover these threehuman enzymes. In parallel, properties known to influence theabsorption, distribution, metabolism, and excretion (ADME)profile of the series were optimized resulting in20gbeingprogressed into an efficacy study in mice. Though20gshowedtoxicity in mice, it also demonstrated CNS penetration in a PKstudy and significant reduction of parasitemia in four out of the sixmice.This work was supported by National Institutes of HealthGrants (R01AI114685 (M.P.P. and M.N.), R01AI082577(M.P.P.), R56AI099476 (M.P.P.), R01AI124046 (M.P.P.),R21AI127594 (M.P.P.), the Spanish Ministerio de Economía,Industria y Competitividad (M.N., Grant SAF2015-71444-P;D.G.P., Grant SAF2016-79957-R., and Subdirección Generalde Redes y Centros de Investigación Cooperativa (RICET)(M.N., Grant RD16/0027/0019; D.G.P., Grant RD16/0027/0014), Grant RTI2018-097210-B-100 (MINCIU-FEDER) toF.G. C.R.C. acknowledges grant support from the NIH-NIAID(Grant R21AI126296) and the Bill and Melinda GatesFoundation (Grant OPP1171488), as well as the technicalassistance of Brian M. Suzuki for screening adultS. mansoni.We are grateful to AstraZeneca for performing thein vitroADME experiments presented throughout and to CharlesRiver Labs for thein vitroADME data presented inTables S3−S5 in the Supporting Information. We thank GSK Tres Cantosopen lab foundation for running the PK studies discussed inthis publication. An academic license for ChemAxon (https://www.chemaxon.com) is gratefully acknowledged. We thankDr. Melissa Buskes for help in the preparation of thismanuscri

6-Arylpyrazine-2-carboxamides : a new core for Trypanosoma brucei inhibitors

From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol(-1)) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported