The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases – plasmepsins (Plms) – are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.
SUBSTITUTED AMINOALKYLAZOLES AS MALARIAL ASPARTIC PROTEASE INHIBITORS
The present invention relates to novel aminoalkylazoles acting as inhibitors of malarial protease plasmepsin II. These can be used as medicines or as constituent of medicines for the treatment of malaria infection.
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Page/Page column 32
(2017/08/01)
Design and synthesis of boronic acid inhibitors of endothelial lipase
Endothelial lipase (EL) and lipoprotein lipase (LPL) are homologous lipases that act on plasma lipoproteins. EL is predominantly a phospholipase and appears to be a key regulator of plasma HDL-C. LPL is mainly a triglyceride lipase regulating (V)LDL levels. The existing biological data indicate that inhibitors selective for EL over LPL should have anti-atherogenic activity, mainly through increasing plasma HDL-C levels. We report here the synthesis of alkyl, aryl, or acyl-substituted phenylboronic acids that inhibit EL. Many of the inhibitors evaluated proved to be nearly equally potent against both EL and LPL, but several exhibited moderate to good selectivity for EL.
O'Connell, Daniel P.,Leblanc, Daniel F.,Cromley, Debra,Billheimer, Jeffrey,Rader, Daniel J.,Bachovchin, William W.
supporting information; experimental part
p. 1397 - 1401
(2012/03/26)
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