Hans Maag

Prodrugs of Carboxylic Acids

Carboxylic acids are often present as a functional group of effective medicines. They are involved in specific charge-charge interactions and are thus often critical for the binding of agents to their targets. The carboxylic acid functional group adds to the hydrophilicity of the drug as well as to its polarity and this may impede the bioavailability. Most carboxylic acids have a pKa value of about 3.5 to 4.5 and thus these compounds are ionized (deprotonated) under physiological conditions. Quite often, the logD values of these agents drop below the range of logD values of well absorbed drugs (logD > 0). These properties of carboxylic acids in active principles has been well recognized for many years and a number of practical solutions have been identified with the most common one being that of the ester modification. This brief review will concentrate on successful prodrug strategies for carboxylic acids, with particular emphasis on compounds which have reached the market, and will not cover ester prodrugs of alcohols and phenols.

Application of the “trimethyl lock”1 to Ganciclovir, a pro-prodrug with increased oral bioavailability☆

Abstract The synthesis and oral bioavailability of two potential prodrugs of Ganciclovir ( 1 ) based on the “trimethyl lock” is described. The mono-3-(2′-Acetoxy-4′6′-dimethylphenyl)-3,3-dimethylpropanoic ester ( 2 ) showed a four-fold increase in oral bioavailability over the parent drug in rats.

Characterization of RO5126946, a novel α7 nicotinic acetylcholine receptor positive allosteric modulator

Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer’s disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946’s effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4β2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine’s effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.

The regioselective opening of 5-O-benzyl-1,2:3,4-O-isopropylidene-D-psicofuranose with organostannanes

Abstract The trimethylsilyl triflate mediated regioselective opening of 5-O-benzyl-1,2:3,4-O-isopropylidene-D-psicofuranose with organostannanes is presented. Hydrolysis of the initially formed 1-O-trimethylsilyl ether yields the products of S- and C-glycosidation with predominantly β-stereochemistry in good yields. The unusual addition of acetonitrile to the intermediate oxonium ion when the reaction is performed in this medium is also outlined.

Case Study: Valganciclovir: A Prodrug of Ganciclovir

Valganciclovir (Valcyte™) is the commercially successful example of a number of prodrugs investigated to improve the oral bioavailability of ganciclovir (Cytovene®), a potent antiviral agent for the treatment of cytomegalovirus (CMV) infections (Markham and Faulds, 1994). Ganciclovir is a fairly polar compound (logP = −1.65) limiting its uptake by passive routes and has moderate solubility in water at pH 7 (6 mg/mL at 37°C). Ganciclovir is supplied in two formulations: a) a intravenous formulation (IV) in the form of a lyophilized powder of the sodium salt to be reconstituted with water and b) a oral tablet formulation (Physician’s Desk Reference 2004). The IV formulation is quite basic and has to be administered slowly in dilute form. The oral formulation is adversely impacted by the physical properties of the compound, resulting in an oral bioavailability of approximately 7%. Therefore, the oral formulation is used mainly for maintenance therapy, while for induction therapy, IV formulations are being used to assure adequate exposure levels.