Owen B. Wallace

HIV-1 entry - an expanding portal for drug discovery.

The advent of highly active antiretroviral therapy (HAART)-combinations of protease and reverse transcriptase inhibitors-provided a potent and clinically effective method of suppressing viral load in HIV-1- infected individuals. However, although initially successful, a broader clinical experience has revealed limitations in this therapeutic regimen, with up to 40% of treated individuals ultimately failing to sustain control over viral replication. Significant advances in understanding the process by which HIV-1 enters host cells have brought into clear focus a target for drug discovery not represented in the current clinical armamentarium. In this article, the mechanism of HIV-1 entry is reviewed in the context of representative antiviral agents that interfere with key steps in this process.

Solid-phase synthesis of N,N′ substituted guanidines☆

Abstract An efficient method for the solid-phase synthesis of substituted guanidines is presented. A variety of alcohols react with resin-bound N,N′-bis(t-butoxycarbonyl)thiopseudourea under Mitsunobu conditions to give the corresponding alkylated thiopseudoureas. The guanidines are liberated from the resin upon exposure to ammonia or primary amines.

Inhibitors of Aβ production: solid-phase synthesis and SAR of α-hydroxycarbonyl derivatives

Inhibitors of amyloid-β (Aβ) protein production have been widely pursued as a potential treatment for Alzheimers disease. Following the identification of a 5 μM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of α-hydroxy esters and ketones which are sub-micromolar inhibitors of Aβ production were identified. The most potent α-hydroxyketone identified is approximately 30-fold more potent than the initial lead.

MILD, SELECTIVE DEPROTECTION OF THIOACETATES USING SODIUM THIOMETHOXIDE

Abstract A mild method for the deprotection of thioacetates is described. The reaction can be conveniently carried out at room temperature, and is compatible with a wide range of functionality. The procedure was shown to chemoselectively remove a thioacetate in the presence of an acetate.

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.

Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity.

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.

Solid phase synthesis of ketones from esters

Abstract A one-pot procedure for the solid phase synthesis of ketones from the corresponding esters, via in situ formation of the N-methoxy-N-methylamide, is described.