Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

Malar J. 2021 Feb 19;20(1):107. doi: 10.1186/s12936-021-03617-1.


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.

Keywords: Bioavailability; Candidate selection; Dose proportional exposure; In vitro and in vivo metabolism; Physicochemical properties.

MeSH terms

  • Animals
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Antimalarials / toxicity
  • Biological Availability
  • Dogs
  • Hepatocytes / drug effects
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / toxicity
  • Humans
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology*
  • Isoquinolines / toxicity
  • Mice
  • Microsomes, Liver / drug effects
  • Rats


  • Antimalarials
  • Heterocyclic Compounds, 4 or More Rings
  • Isoquinolines
  • SJ733