(+)-SJ733   Click here for help

GtoPdb Ligand ID: 9723

Synonyms: (+)-SJ000557733 | (+)-SJ557733
Antimalarial Ligand
Compound class: Synthetic organic
Comment: (+)-SJ733 is the optimized lead for the dihydroisoquinolones (DHIQ), a novel chemotype with antimalarial activity [2].
The (+)-enantiomer, shown here, has a significantly higher antimalarial potency [2].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 86.09
Molecular weight 468.12
XLogP 3.8
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES N#Cc1cc(ccc1F)NC(=O)C1c2ccccc2C(=O)N(C1c1cccnc1)CC(F)(F)F
Isomeric SMILES N#Cc1cc(ccc1F)NC(=O)[C@H]1c2ccccc2C(=O)N([C@@H]1c1cccnc1)CC(F)(F)F
InChI InChI=1S/C24H16F4N4O2/c25-19-8-7-16(10-15(19)11-29)31-22(33)20-17-5-1-2-6-18(17)23(34)32(13-24(26,27)28)21(20)14-4-3-9-30-12-14/h1-10,12,20-21H,13H2,(H,31,33)/t20-,21+/m0/s1
InChI Key VKCPFWKTFZAOTO-LEWJYISDSA-N
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Summary of Clinical Use Click here for help
(+)-SJ733 has completed Phase 1 trials, demonstrating a favourable pharmacokinetic, tolerability, and safety profile combined with rapid parasite clearance [1].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
The exact mechanism of action of (+)-SJ733 is not fully understood but Plasmodium non-SERCA-type Ca2+-transporting P-ATPase (PfATP4) may be the potential target because mutatations in PfATP4 confer resistance to this compound [2]. (+)-SJ733 produces a rapid perturbation of parasitic intracellular Na+ levels, in concurrence with the proposed role of PfATP4 in the regulation of Na+ homeostasis, followed by physical changes in the infected erythrocytes. It has been proposed that host-mediated clearance of infected cells may be responsible for the rapid action of PfATP4 inhibitors [2].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02867059 SJ733 Induced Blood Stage Malaria Challenge Study Phase 1 Interventional Medicines for Malaria Venture 1
NCT02661373 First-in-Human Study of an Oral Plasmodium Falciparum Plasma Membrane Protein Inhibitor Phase 1 Interventional St. Jude Children's Research Hospital 1