779299-76-2

Upstream product

• 160232-08-6 (2R,3S)-3-tert-butoxycarbonylamino-1-isobutylamino-4-phenyl-2-butanol 
• 98760-08-8 (1-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester 
• 160232-85-9 N-[(1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[[(4-trifluoromethoxy)phenyl]sulfonyl]amino]propyl]carbamic acid tert-butyl ester 

Relevant academic research and scientific papers

Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2?ligand: Structure?activity studies and biological evaluation

The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).

Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands

Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with Ki values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (Ki = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar Ki, which is highly comparable with the best FDA-approved protease inhibitors.