scholarly journals Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

2020 ◽  
Author(s):  
Yizhe Chen ◽  
Fangyi Zhu ◽  
Jared Hammill ◽  
Gloria Holbrook ◽  
Lei Yang ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Oral Bioavailability ◽  
Cost Effective ◽  
Therapeutic Index ◽  
Cross Resistance ◽  
Human Cytochrome ◽  
Eradication Campaign ◽  
Effective Drugs ◽  
Clinical Candidate

Abstract Background The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. Herein we present the process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles. Methods The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma and microsomal proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome p450 inhibition were assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Results Both compounds displayed similar physicochemical properties, but SJ733 was more permeable and metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. Conclusion SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

scholarly journals Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yizhe Chen ◽  
Fangyi Zhu ◽  
Jared Hammill ◽  
Gloria Holbrook ◽  
Lei Yang ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Oral Bioavailability ◽  
Cost Effective ◽  
Therapeutic Index ◽  
Cross Resistance ◽  
Human Cytochrome ◽  
Eradication Campaign ◽  
Effective Drugs ◽  
Clinical Candidate

Abstract Background The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. Methods The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Results Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. Conclusion SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

scholarly journals Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

2021 ◽  
Author(s):  
Yizhe Chen ◽  
Fangyi Zhu ◽  
Jared Hammill ◽  
Gloria Holbrook ◽  
Lei Yang ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Oral Bioavailability ◽  
Cost Effective ◽  
Therapeutic Index ◽  
Cross Resistance ◽  
Human Cytochrome ◽  
Eradication Campaign ◽  
Effective Drugs ◽  
Clinical Candidate

Abstract Background: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. Herein we present the process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles. Methods: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Results: Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. Conclusion: SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

scholarly journals 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1997 ◽  
Vol 41 (5) ◽  
pp. 1082-1093 ◽  
Author(s):  
S M Daluge ◽  
S S Good ◽  
M B Faletto ◽  
W H Miller ◽  
M H St Clair ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Bioavailability ◽  
Human Peripheral Blood ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Carbocyclic Nucleoside ◽  
Hiv 1 ◽  
In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

In vitro assessment of mineral blocks as a cost-effective measure to reduce oral bioavailability of lead (Pb) in livestock

2020 ◽  
Vol 27 (20) ◽  
pp. 25563-25571 ◽  
Author(s):  
Jennifer Pareja-Carrera ◽  
Jaime Rodríguez-Estival ◽  
Rafael Mateo ◽  
Mónica Martinez-Haro
Keyword(s):  
Oral Bioavailability ◽  
Cost Effective ◽  
Effective Measure ◽  
In Vitro Assessment ◽  
Cost Effective Measure

scholarly journals Fabrication of Carbamazepine Cocrystals: Characterization, In Vitro and Comparative In Vivo Evaluation

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Muhammad Wasim ◽  
Abdul Mannan ◽  
Muhammad Hassham Hassan Bin Asad ◽  
Muhammad Imran Amirzada ◽  
Muhammad Shafique ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Oral Bioavailability ◽  
In Vivo Studies ◽  
Aliphatic Chain ◽  
Dissolution Profile ◽  
Maximum Solubility ◽  
In Vivo Evaluation ◽  
Hydrophobic Nature

Carbamazepine (CBZ) is an antiepileptic drug having low bioavailability due to its hydrophobic nature. In the current study, efforts are made to investigate the effect of dicarboxylic acid coformer spacer groups (aliphatic chain length) on physicochemical properties, relative humidity (RH) stability, and oral bioavailability of CBZ cocrystals. Slurry crystallization technique was employed for the preparation of CBZ cocrystals with the following coformers: adipic (AA), glutaric (GA), succinic (SA), and malonic acid (MA). Powder X-ray diffractometry and Fourier-transform infrared spectroscopy confirmed cocrystal preparation. Physicochemical properties, RH stability, and oral bioavailability of cocrystals were investigated. Among the prepared cocrystals, CBZ-GA showed maximum solubility as well as improved dissolution profile (CBZ-GA > CBZ-MA > CBZ-AA > pure CBZ > CBZ-SA) in ethanol. Maximum RH stability was shown by CBZ-AA, CBZ-SA, and CBZ-MA. In vivo studies confirmed boosted oral bioavailability of cocrystals compared to pure CBZ. Furthermore, in vivo studies depicted the oral bioavailability order of cocrystals as CBZ-GA > CBZ-MA > Tegral® > CBZ-AA > CBZ-SA > pure CBZ. Thus, pharmaceutical scientists can effectively employ cocrystallization technique for tuning physicochemical properties of hydrophobic drugs to achieve the desired oral bioavailability. Overall, results reflect no consistent effect of spacer group on physicochemical properties, RH stability, and oral bioavailability of cocrystals.

scholarly journals The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Stephen Patterson ◽  
Susan Wyllie ◽  
Suzanne Norval ◽  
Laste Stojanovski ◽  
Frederick RC Simeons ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Dose Response ◽  
Leishmania Donovani ◽  
Oral Treatment ◽  
Cost Effective ◽  
Resistant Tuberculosis ◽  
Multi Drug Resistant Tuberculosis ◽  
Effective Drugs

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.

scholarly journals Mitigate the cytokine storm due to the severe COVID-19: A computational investigation of possible allosteric inhibitory actions on IL-6R and IL-1R using selected phytochemicals

2020 ◽  
Vol 11 (4) ◽  
pp. 351-363
Author(s):  
Harindu Rajapaksha ◽  
Bingun Tharusha Perera ◽  
Jeewani Meepage ◽  
Ruwan Tharanga Perera ◽  
Chithramala Dissanayake
Keyword(s):  
Conformational Changes ◽  
Oral Bioavailability ◽  
Interleukin 1 ◽  
Extensive Literature ◽  
The Novel ◽  
Cytokine Storm ◽  
Allosteric Sites ◽  
Life Threatening ◽  
Effective Drugs

The novel corona virus 2019 (COVID 19) is growing at an increasing rate with high mortality. Meanwhile, the cytokine storm is the most dangerous and potentially life-threatening event related to COVID 19. Phyto-compounds found in existing Ayurveda drugs have the ability to inhibit the Interleukin 6 (IL-6R) and Interleukin 1 (IL-1R) receptors. IL-6R and IL-1R receptors involve in cytokine storm and recognition of phytochemicals with proven safety profiles could open a pathway to the development of the most effective drugs against cytokine storm. In this study, we intend to perform an in silico investigation of effective phyto compounds, which can be isolated from selected medicinal herbs to avoid cytokine storm, inhibiting the IL-6 and IL-1 receptor binding process. An extensive literature survey followed by virtual screening was carried out to identify phytochemicals with potential anti-hyper-inflammatory action. Flexible docking was conducted for validated models of IL-1R and IL-6R-α with the most promising phytochemicals at possible allosteric sites using AutoDock Vina. Molecular dynamics (MD) studies were conducted for selected protein-ligand complexes using LARMD server and conformational changes were evaluated. According to the results, taepeenin J had Gibbs energy (ΔG) of -10.85 kcal/mol towards IL-1R but had limited oral bioavailability. MD analysis revealed that taepeenin J can cause significant conformational movements in IL-1R. Nortaepeenin B showed a ΔG of -8.5 kcal/mol towards IL-6R-α with an excellent oral bioavailability. MD analysis predicted that it can cause significant conformational movements in IL-6R-α. Hence, the evaluated phytochemicals are potential candidates for further in vitro studies for the development of medicine against cytokine storm on behalf of SARS-COV-2 infected patients.

Human cytochrome P450 enzyme inhibition profile of three flavonoids isolated from Psoralea corylifolia: in silico predictions and experimental validation

2018 ◽  
Vol 42 (13) ◽  
pp. 10922-10934 ◽  
Author(s):  
Lili Wang ◽  
Yue Hai ◽  
Nannan Huang ◽  
Xue Gao ◽  
Wenli Liu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Experimental Validation ◽  
Cost Effective ◽  
Cytochrome P450 Enzyme ◽  
Psoralea Corylifolia ◽  
Human Cytochrome ◽  
P450 Enzyme ◽  
Human Cytochrome P450 Enzyme ◽  
Clinical Drug

Cytochrome P450 enzyme (CYP)-associated metabolic studies in vitro have been considered cost-effective for predicting potential clinical drug/herb–drug interactions (DDI/HDI).

scholarly journals Partitioning of cancer therapeutics in nuclear condensates.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3131-3131
Author(s):  
Isaac Klein ◽  
Ann Boija ◽  
Lena Afeyan ◽  
Susana Hawken ◽  
Mengyang Fan ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Small Molecule ◽  
Cancer Therapeutics ◽  
Therapeutic Index ◽  
Regulatory Elements ◽  
Specific Protein ◽  
Target Engagement ◽  
Membrane Bound ◽  
In Cells

3131 Background: The molecules of the cell are compartmentalized into membrane- and non-membrane-bound organelles. Many non-membrane-bound organelles are phase-separated biomolecular condensates with distinct physicochemical properties that can absorb and concentrate specific proteins and nucleic acids involved in discrete biochemical processes. We reasoned that selective condensate partitioning might also occur with small molecule drugs whose targets occur within condensates, and that the therapeutic index and efficacy of such compounds might therefore relate to their ability to partition into condensates. Methods: To study the behavior of drugs within condensates, these were modeled in cells and in vitro with purified proteins and visualized by fluorescent confocal microscopy. The functional outcomes of condensate partitioning were queried in cells. Results: We found that cisplatin, tamoxifen, JQ1, THZ1, and mitoxantrone are concentrated in specific protein condensates in vitro, and that this occurs through physicochemical properties independent of the drug target. A screen of a chemically diverse fluorescent probes and mutant-protein condensates demonstrated that pi-system interactions between aromatic moieties in the protein and small molecule govern concentration in condensates. These results show that clinically important drugs partition into specific protein condensates in vitro by virtue of defined chemical properties, thereby altering their local concentration. In vitro droplet assays revealed that cisplatin is selectively concentrated in transcriptional condensates, and that this ability is required for efficient platination of target DNA. In cell studies revealed that cisplatin preferentially targets DNA contained within MED1 condensates, and disrupts the genetic regulatory elements that compose phase-separated transcriptional condensates. Live cell imaging demonstrated that transcriptional condensates are dissolved by cisplatin, whereas other condensates remain intact. Conclusions: Our results show that antineoplastic drugs partition selectively into biomolecular condensates, that this can occur through physicochemical properties independent of their molecular targets, and that drug activity may occur through condensate-related mechanisms. These results have implications for development of efficacious cancer therapeutics; effective target engagement will depend on factors such as drug partitioning in condensates. Assays of the type described here may thus help optimize condensate partitioning, target engagement, and the therapeutic index of drugs for cancer treatment.

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