CYCLIC SULFONE-3-CARBOXAMIDES AS NOVEL P2-LIGANDS FOR Ro 31-8959 BASED HIV-1 PROTEASE INHIBITORS.

Cyclic sulfone-3-carboxamides are effective P2-1igands for HIV-1 protease inhibitors. Incorporation of 3S-tetrahydro-2H-thiopyrancarboxamide-l, l-dioxide in the hydroxyethylamine series resulted in inhibitor 14 (IC50=9 nM, CIC95=200 nM) with improved potency compared to its corresponding urethane derivative 18 (IC50=2.0 µM).

Potent HIV-1 Protease Inhibitors: Stereoselective Synthesis of a Dipeptide Mimic.

The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.

3'-Tetrahydrofuranylglycine as a Novel, Unnatural Amino Acid Surrogate for Asparagine in the Design of Inhibitors of the HIV Protease.

The blockade of the HIV protease has become a major target in the search for an effective therapy for AIDS.1 While many reports of potent HIV-1 inhibitors have appeared recently, the compound Ro 31-8959 remains the least selective for the HIV-1 and HIV-2 proteases.2 This property may result in reduced susceptibility to resistance since these represent the genetically most divergent strains of HIV presently known to exist.

An Efficient Synthesis of Functionalized Urethanes from Azides.

Catalytic hydrogenation of various azides in the presence of functionalized mixed carbonates afforded the corresponding urethanes in high yields.

N,N'-Disuccinimidyl Carbonate: A Useful Reagent for Alkoxycarbonylation of Amines.

An efficient and mild method for alkoxycarbonylation of amines is described, utilizing commercially available N,N'-disuccinimidyl carbonate.

A Facile and Enantiospecific Synthesis of 2(S)- and 2(R)-[1'(S)-Azido-2-phenylethyl]oxirane.

The title azidoalkyl oxiranes were synthesized efficiently in an enantiomerically pure form utilizing readily available diethyl d-tartrate.

STEREOCONTROLLED SYNTHESIS OF HIV-l PROTEASE INHIBITORS WITH C2-AXIS OF SYMMETRY.

An efficient and stereocontrolled synthesis of various C2-symmetric HIV-l protease inhibitors is described, starting from commercially available and inexpensive D-mannitol.

An Efficient Synthesis of Hydroxyethylene Dipeptide Isosteres: The Core Unit of Potent HIV-1 Protease Inhibitors.

An efficient and stereocontrolled synthesis of hydroxyethylene dipeptide isosteres 1 from commercially available, optically pure D-mannose is described. This synthesis represents a practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited to amino acid derived substituents.