Ts. Haque et al., Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II, J MED CHEM, 42(8), 1999, pp. 1428-1440
A number of single-digit nanomolar, low-molecular-weight plasmepsin II aspa
rtyl protease inhibitors have been identified using combinatorial chemistry
and structure-based design. By identifying multiple, small-molecule inhibi
tors using the parallel synthesis of several focused libraries, it was poss
ible to select for compounds with desirable characteristics including enzym
e specificity and minimal binding to serum proteins. The best inhibitors id
entified have Ki's of 2-10 nM, molecular weights between 594 and 650 Da, be
tween 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 vit
ro assay. These compounds represent the most potent non-peptide plasmepsin
II inhibitors reported to date.