Nine of 16 stereoisomeric polyhydroxylated proline amides are potent ß-N-acetylhexosaminidase inhibitors.

All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of ß-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. ß-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.

2-N-Benzyl-2,6-dide-oxy-2,6-imino-3,4-O-iso-propyl-idene-d-allono-nitrile.

X-ray crystallography firmly established the relative stereochemistry of the title compound, C16H20N2O3. The acetonide ring adopts an envelope conformation with one of the O atoms as the flap and the piperidine ring adopts a slightly twisted boat conformation. The absolute configuration was determined by use of d-ribose as the starting material. The compound exists as O-H⋯O hydrogen-bonded chains of mol-ecules running parallel to the b axis.

Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: the effect of N-alkylation on hexosaminidase inhibition.

The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of ß-GlcNAcases and ß-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.

Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone.

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase.

2-N-Benzyl-2,6-dide-oxy-2,6-imino-3,4-O-isopropyl-idene-3-C-methyl-d-allono-nitrile.

X-ray crystallography firmly established the relative stereochemistry of the title compound, C(17)H(22)N(2)O(3). The absolute configuration was determined by use of 2-C-methyl-d-ribonolactone as the starting material. The compound exists as O-H⋯N hydrogen-bonded chains of mol-ecules running parallel to the a-axis.

First-in-Human Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Rapidly Developed SARS-CoV-2 Therapeutic Antibody, AOD01, in Healthy Adults.

INTRODUCTION: AOD01 is a novel, fully human immunoglobulin (Ig) G1 neutralizing monoclonal antibody that was developed as a therapeutic against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AOD01 in healthy volunteers. METHODS: Intravenous doses of AOD01 were evaluated in escalating cohorts [four single-dose cohorts (2, 5, 10, and 20 mg/kg) and one two-dose cohort (two doses of 20 mg/kg, 24 h apart)]. RESULTS: Twenty-three subjects were randomized to receive AOD01 or a placebo in blinded fashion. A total of 34 treatment-emergent adverse events (TEAEs) were reported; all were mild in severity. Related events (headache and diarrhea) were reported in one subject each. No event of infusion reactions, serious adverse event (SAE), or discontinuation due to AE were reported. The changes in laboratory parameters, vital signs, and electrocardiograms were minimal. Dose-related exposure was seen from doses 2 to 20 mg/kg as confirmed by Cmax and AUC0-tlast. The median Tmax was 1.5-3 h. Clearance was dose independent. Study results revealed long half-lives (163-465 h). Antidrug antibodies (ADA) to AOD01 were not detected among subjects, except in one subject of the two-dose cohort on day 92. Sustained ex vivo neutralization of SARS-CoV-2 was recorded until day 29 with single doses from 2 to 20 mg/kg and until day 43 with two doses of 20 mg/kg. CONCLUSIONS: AOD01 was safe and well tolerated, demonstrated dose-related PK, non-immunogenic status, and sustained ex vivo neutralization of SARS-CoV-2 after single intravenous dose ranging from 2 to 20 mg/kg and two doses of 20 mg/kg and show good potential for treatment of SARS-CoV-2 infection. (Health Sciences Authority identifier number CTA2000119).

Iteamine, the first alkaloid isolated from Itea virginica L. inflorescence.

Iteamine, o-aminobenzyl ß-D-glucopyranoside, is the first alkaloid to be isolated from Itea virginica. Itea is the sole plant source of D-psicose, a rare sugar likely to be a major dietary supplement. The structure of iteamine was established by NMR and confirmed by total synthesis. Iteamine and its galacto-analog (which was not found in Itea plants) showed no strong inhibition of any of the 15 glycosidases tested; unnatural galacto-iteamine was a weak inhibitor of chicken liver α-N-acetylgalactosaminidase.