Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones
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...
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doaj-ab8cf99d57bd45dc8262fb7f25bbd8842021-02-21T12:46:26ZengBMCMalaria Journal1475-28752021-02-0120111510.1186/s12936-021-03617-1Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolonesYizhe Chen0Fangyi Zhu1Jared Hammill2Gloria Holbrook3Lei Yang4Burgess Freeman5Karen L. White6David M. Shackleford7Kathleen G. O’Loughlin8Susan A. Charman9Jon C. Mirsalis10R. Kiplin Guy11Department of Pharmaceutical Sciences, University of Kentucky College of PharmacyDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Pharmaceutical Sciences, University of Kentucky College of PharmacyDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalPreclinical Pharmacokinetics Shared Resource, St. Jude Children’s Research HospitalCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash UniversityCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash UniversityToxicology and Pharmacokinetics, SRI InternationalCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash UniversityToxicology and Pharmacokinetics, SRI InternationalDepartment of Pharmaceutical Sciences, University of Kentucky College of PharmacyAbstract 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.https://doi.org/10.1186/s12936-021-03617-1Candidate selectionPhysicochemical propertiesIn vitro and in vivo metabolismBioavailabilityDose proportional exposure |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yizhe Chen Fangyi Zhu Jared Hammill Gloria Holbrook Lei Yang Burgess Freeman Karen L. White David M. Shackleford Kathleen G. O’Loughlin Susan A. Charman Jon C. Mirsalis R. Kiplin Guy |
spellingShingle |
Yizhe Chen Fangyi Zhu Jared Hammill Gloria Holbrook Lei Yang Burgess Freeman Karen L. White David M. Shackleford Kathleen G. O’Loughlin Susan A. Charman Jon C. Mirsalis R. Kiplin Guy Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones Malaria Journal Candidate selection Physicochemical properties In vitro and in vivo metabolism Bioavailability Dose proportional exposure |
author_facet |
Yizhe Chen Fangyi Zhu Jared Hammill Gloria Holbrook Lei Yang Burgess Freeman Karen L. White David M. Shackleford Kathleen G. O’Loughlin Susan A. Charman Jon C. Mirsalis R. Kiplin Guy |
author_sort |
Yizhe Chen |
title |
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
title_short |
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
title_full |
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
title_fullStr |
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
title_full_unstemmed |
Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
title_sort |
selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones |
publisher |
BMC |
series |
Malaria Journal |
issn |
1475-2875 |
publishDate |
2021-02-01 |
description |
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. |
topic |
Candidate selection Physicochemical properties In vitro and in vivo metabolism Bioavailability Dose proportional exposure |
url |
https://doi.org/10.1186/s12936-021-03617-1 |
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