Deferitazole, a new orally active iron chelator.

Following a systematic search of desferrithiocin analogs, a polyether derivative, deferitazole (formerly FBS0701), has entered into phase 1 and 2 clinical trials with promising biological properties. However, until now, detailed physicochemical properties of this chelator have not been reported. The compound displays a high affinity and selectivity for iron(III) as demonstrated by the log β2 = 33.

trans-2-Tritylcyclohexanol as a chiral auxiliary in permanganate-mediated oxidative cyclization of 2-methylenehept-5-enoates: application to the synthesis of trans-(+)-linalool oxide.

The permanganate-mediated oxidative cyclization of a series of 2-methylenehept-5-eneoates bearing different chiral auxiliaries was investigated, leading to the discovery of trans-2-tritylcyclohexanol (TTC) as a highly effective chiral controller for the formation of the 2,5-substituted THF diol product with high diastereoselectivity (dr ∼97:3). Chiral resolution of (±)-TTC, prepared in one step from cyclohexene oxide, afforded (-)-(1S,2R)-TTC (er >99:1), which was applied to the synthesis of (+)-trans-(2S,5S)-linalool oxide.

Unusual structure-genotoxicity relationship in mouse lymphoma cells observed with a series of kinase inhibitors.

During development of a novel kinase inhibitor for an anti-inflammatory therapy at AstraZeneca UK, the lead compound was found to be potently active in the mouse lymphoma assay (MLA). This was not believed to be due to primary pharmacology because structural alert relationships and a negative Ames test indicated that the compound was unlikely to form DNA adducts. A number of investigations were performed to assess whether mammalian cell genotoxicity was inherent to the chemical series.

In silico prediction of acyl glucuronide reactivity.

Drugs and drug candidates containing a carboxylic acid moiety, including many widely used non-steroidal anti-inflammatory drugs (NSAIDs) are often metabolized to form acyl glucuronides (AGs). NSAIDs such as Ibuprofen are amongst the most widely used drugs on the market, whereas similar carboxylic acid drugs such as Suprofen have been withdrawn due to adverse events. Although the link between these AG metabolites and toxicity is not proven, there is circumstantial literature evidence to suggest that more reactive acyl glucuronides may, in some cases, present a greater risk of exhibiting toxic effects.

Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981.

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules.

A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity.

Lipophilicity of acidic compounds: impact of ion pair partitioning on drug design.

In drug discovery projects the ability to show a relationship between a compound's molecular structure and its pharmacokinetic, in vivo efficacy, or toxicity profile is paramount for the design of better analogues. To aid this understanding the measurement of distribution coefficients at some physiologically relevant pH, for example, log D(7.4), is common practice as they are used as a key descriptor in mathematical models for predicting various biological parameters.

Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids.

A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action.

Zwitterionic CRTh2 antagonists.

A novel series of zwitterions is reported that contains potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A high quality lead compound 2 was discovered from virtual screening based on the pharmacophore features present in a literature compound 1. Lead optimization through side chain modification and preliminary changes around the acid are disclosed.

Prediction of efficacious inhalation lung doses via the use of in silico lung retention quantitative structure-activity relationship models and in vitro potency screens.

Lung concentrations of a drug are expected to drive the pharmacodynamic response to local inflammation after inhalation delivery, and the only way of determining the efficacious dose has been to measure it directly in animal models. In this study, we present a method to predict efficacious lung doses after inhalation in a rat lipopolysaccharide challenge model from in silico predictions of lung concentration and in vitro measurements only. A quantitative structure-activity relationship (QSAR) model, based on calculated physical properties predicted the partitioning of 34 compounds between lung and plasma.

Molybdenum-mediated carbonylation of aryl halides with nucleophiles using microwave irradiation.

A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to excellent yields.

Enantioselective formal synthesis of eurylene: synthesis of the cis- and trans-THF fragments using oxidative cyclization.

A formal synthesis of eurylene is described, where both cis- and trans-THF-containing fragments were prepared using diastereo- and chemoselective permanganate-mediated oxidative monocyclizations of trienes.

Permanganate oxidation of 1,5,9-trienes: stereoselective synthesis of tetrahydrofuran-containing fragments.

Permanganate oxidation of farnesoate esters 12a-d afforded perhydro-2,2'-bifuranyl compounds 16a-d, with control of relative stereochemistry at four new stereocenters. Subsequent oxidative cleavage of 16a-d then provided tetrahydrofuran-containing fragments 17a-d, one of them 17b possessing the same relative stereochemistry present in the C13-C21 portion of the polyether antibiotic semduramycin (1). Control of the absolute stereochemistry was achieved through the use of the Oppolzer sultam chiral auxiliary.

Synthesis and Further Reactivity of Functionalized Lactam-Derived Enol Triflates.

Pyrrolidinone- and piperidinone-derived enol triflates 2 were prepared in high yield (60-97%) from the corresponding lactams 1 using KHMDS and N-(5-chloro-2-pyridyl)triflimide. A structure-stability study on the less stable pyrrolidinone-derived triflates revealed that an N-tosyl group is essential, and an alpha-ethoxy substituent enhances thermal stability. Substituents at the 3- and 4-position are tolerated.