Wayne J. Thompson

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.

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.

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.

Stereocontrolled synthesis of HIV-1 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.

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).

A stereocontrolled synthesis of trans-allylic amines

Abstract The palladium catalyzed coupling of allylic acetates with carbon nucleophiles generates urethane protected trans-allylic amines with exceptionally high stereoselectivity.

Design and synthesis of N-alkylated saccharins as selective α-1a adrenergic receptor antagonists☆

Abstract Benign prostatic hyperplasia can be managed pharmacologically with α-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the α-1 a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective α-1 a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.

Stereoselective synthesis of the hydroxyethylene isostere of the HIV protease (TYR-PRO) cleavage site

Abstract The stereoselective, syntheses and IC 50 s of Tyr-HE-Pro based inhibitors are reported. The [2S,3S,4S,5S]-stereochemistry was preferred by HIV-1 protease.

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.

HIV-1 protease inhibitory activity of L-694,746, a novel metabolite of L-689,502

L-689,502 is a potent inhibitor of HIV-1 protease activity in vitro. Microbial biotransformations of L-689,502 by cultures belonging to the genus Streptomyces sp. were performed. Extracts of culture broths were examined for the production of metabolites of L-689,502 that could inhibit HIV-1 protease activity. One culture, MA 6804 (Streptomyces lavendulae, ATCC 55095), produced L-694,746 that, while being structurally related to L-689,502, is a novel metabolite and a potent inhibitor of HIV-1 protease.