Efficient method to prepare hydroxyethylamine-based aspartyl protease inhibitors with diverse P1 side chains

Chino, Masao; Wakao, Masahiro; Ellman, Jonathan A.

doi:10.1016/s0040-4020(02)00629-4

Cited by 12 publications

(7 citation statements)

References 18 publications

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“…STEP 1: This procedure was adapted from a prior publication 42. Isobutylchloroformate (1.1 equiv) was added to a 0.1 M solution of the azido acid43 (1 equiv) and N -methyl morpholine (1.1 equiv) in THF at −40 °C.…”

Section: Methodsmentioning

confidence: 99%

Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

et al. 2010

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A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogs with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogs in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.

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Section: Methodsmentioning

confidence: 99%

Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

et al. 2010

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“…In addition, in the syntheses of inhibitors containing hydroxy-type isosters, formation of the byproducts derived from overreaction at the hydroxy group yielded homobislactone or a half-ester dimer . To avoid these limitations, several solid-phase approaches were reported, in which a multistep conversion of the functional groups would be necessary for the chain elongation due to the acid-labile linkage to the solid support . A key feature of our solid-phase approach is the development of an acid-stable linker, which can be incorporated by simple reaction with succinic anhydride.…”

Section: Resultsmentioning

confidence: 99%

Solid-Phase Synthesis of HTLV-1 Protease Inhibitors Containing Hydroxyethylamine Dipeptide Isostere

2003

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An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure-activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the K(i) value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.

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“…The syntheses of compounds 8a‐c are summarized in Scheme 1. The protected phenylalanine 3 was converted to the chloromethyl ketone 4 by treating the diazoketone intermediate with hydrochloric solution in ether (10). Chelation‐controlled reduction of ketone by LiAlH(OtBu) 3 in ethanol at −78 °C gave a greater degree of diastereoselectivity to the erythro chlorohydrin (17).…”

Section: Methodsmentioning

confidence: 99%

“…Most efforts on developing new PIs have been focused on designing various P 2 –P 3 and P 2 ′groups, which were expected to possess high affinity to HIV‐1 PR (8–12). Based on a rationale of mimicking its substrate for PR, several ligands with high affinity were discovered, some of which are shown in Figure 1.…”

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confidence: 99%

Design, Biologic Evaluation, and SAR of Novel Pseudo‐peptide Incorporating Benzheterocycles as HIV‐1 Protease Inhibitors

Zhang

Yao

et al. 2010

Chem Biol Drug Des

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A series of novel HIV‐1 protease inhibitors based on the (hydroxyethylamino)‐sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the ‐CH2‐ of P1‐P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV‐1 protease with an IC50 value of 5 nm, also exhibited good anti‐SIV activity (EC50 = 0.8 μm) with low toxicity (TC50 > 100 μm). The flexible docking of inhibitor 23 to HIV‐1 protease active site rationalized the interactions with protease.

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Efficient method to prepare hydroxyethylamine-based aspartyl protease inhibitors with diverse P1 side chains

Cited by 12 publications

References 18 publications

Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy

Solid-Phase Synthesis of HTLV-1 Protease Inhibitors Containing Hydroxyethylamine Dipeptide Isostere

Design, Biologic Evaluation, and SAR of Novel Pseudo‐peptide Incorporating Benzheterocycles as HIV‐1 Protease Inhibitors

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