Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II

Tasir S. Haque, A. Geoffrey Skillman, Christina E. Lee, Hiromu Habashita, Ilya Y. Gluzman, Todd J.A. Ewing, Daniel E. Goldberg, Irwin D. Kuntz, Jonathan A. Ellman

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171 Scopus citations


A number of single-digit nanomolar, low-molecular-weight plasmepsin II aspartyl protease inhibitors have been identified using combinatorial chemistry and structure-based design. By identifying multiple, small-molecule inhibitors using the parallel synthesis of several focused libraries, it was possible to select for compounds with desirable characteristics including enzyme specificity and minimal binding to serum proteins. The best inhibitors identified have K(i)'s of 2-10 nM, molecular weights between 594 and 650 Da, between 3- and 15-fold selectivity toward plasmepsin II over cathepsin D, the most closely related human protease, good calculated log P values (2.86- 4.56), and no apparent binding to human serum albumin at 1 mg/mL in an in vitro assay. These compounds represent the most potent non-peptide plasmepsin II inhibitors reported to date.

Original languageEnglish
Pages (from-to)1428-1440
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number8
StatePublished - Apr 22 1999


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