99113-35-6Relevant articles and documents
Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D
Zogota, Rimants,Kinena, Linda,Withers-Martinez, Chrislaine,Blackman, Michael J.,Bobrovs, Raitis,Pantelejevs, Teodors,Kanepe-Lapsa, Iveta,Ozola, Vita,Jaudzems, Kristaps,Suna, Edgars,Jirgensons, Aigars
, p. 344 - 352 (2018/12/11)
Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.
From L-ascorbic acid to protease inhibitors: Practical synthesis of key chiral epoxide intermediates for aspartyl proteases
Chang, Sun Ki,So, Soon Mog,Lee, Sang Min,Kim, Min Kyu,Seol, Kyoung Mee,Kim, Sung Min,Kang, Jae Sung,Choo, Dong Joon,Lee, Jae Yeol,Kim, B. Moon
experimental part, p. 2213 - 2218 (2012/09/21)
Efficient synthetic routes were developed to prepare a sizable amount (4-15 grams) of the chiral epoxides 4-6 as versatile intermediates for the synthesis of aspartyl protease inhibitors of therapeutic interest such as HIV protease and β-secretase. Oxidative cleavage of the C(2)-C(3) double bond of L-ascorbic acid followed by functional group manipulation led to the preparation of the epoxide 10, which was opened with an azide to yield a common aziridine intermediate 12. Through opening of the aziridine ring of 12 with either a carbon or a sulfur nucleophile, chiral epoxide precursors 4-6 could be prepared for various HIV protease inhibitors. Except for the final low melting epoxides 5 and 6, all intermediates were obtained as crystalline solids, thus the synthetic pathway can be easily applied to a large-scale synthesis of the chiral epoxides.
Application of the lewis acid-lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: Stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and β3- adenergic receptor agonist
Nogami, Hiroyuki,Kanai, Motomu,Shibasaki, Masakatsu
, p. 702 - 709 (2007/10/03)
Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97:3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of β3-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to β-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.
