ChemMedChem

The cover picture shows aspirin docked in the active site of ovine COX-1. According to the results of this QM/MM study, this is the conformation likely to trigger Ser 530 acetylation under general base catalysis by the carboxylate group of aspirin. The hydroxy group of Tyr 385 proved to play a key role in orienting and polarizing the acetyl moiety, as previously postulated by Hochgesang et al. on the basis of site-directed mutagenesis experiments. For more details, see the Communication by P. Tosco and L. Lazzarato on p. 939 ff.

The inside cover picture shows the X-ray-determined binding of an α-ethoxy-phenyl-propionic acid-derived dual PPARα/γ agonist in complex with PPARα (yellow) and PPARγ (blue). The high α-selectivity of this phenylthiazole (IC₅₀ γ/α = 37; EC₅₀ γ/α = 7) can be rationalized mainly by a single residue difference, Cys 275 (α) vs. Gly 284 (γ), leading to three additional interactions with the terminal p-Cl-Ph group. In addition, its binding site is highlighted in a surface representation of the PPARα protein. For more details, see the Communication by U. Grether et al. on p. 951 ff.

An international affair: The Medicinal Chemistry Division of the Italian Chemical Society took the bold decision to hold the XIXth National Meeting on Medicinal Chemistry in English. The result was a truly international conference, with delegates and speakers from around the world. This comprehensive report highlights the presentations and awards given.

Frontal affinity chromatography coupled to mass spectrometry (FAC–MS) has been reported as a potential method for screening compound mixtures against immobilized target proteins. The potentiality of this analytical approach is described and illustrated with a number of examples based on targets of pharmaceutical interest.

New glutamate receptor ligands: This review describes the discovery of rationally designed AMPA and NMDA receptor antagonists, some of which have been proven to be highly potent anticonvulsant and neuroprotective agents.

Confidence in mechanism: Creating a more holistic understanding of disease pathophysiology and an early confidence in the mechanism under investigation could help facilitate the selection of not only the most appropriate targets but also the best mechanisms for disease intervention and how to select and optimise the best compounds.

Novel 2-phenylquinolones aimed at the Tat–TAR complex were synthesized and tested. Derivatives characterized by precise modifications of the quinolone nucleus and to the side chain of the 2-phenyl ring allowed a thorough structure–activity study, confirming 2-phenylquinolone as a suitable scaffold for inhibition of the Tat–TAR interaction.

A mechanistic hypothesis for the acetylation of cyclooxygenase (COX) by aspirin is proposed on the basis of a QM/MM study. This mechanism is consistent with previous experimental findings by other investigators. Ser 530 appears to be acetylated under intramolecular general base catalysis provided by the carboxylate moiety of aspirin, while Tyr 385 plays a crucial role in orienting and polarizing the acetyl group.

Biosynthesis Inhibition: O-5596, a new inhibitor of the biosynthesis of the endocannabinoid, 2-arachidonoylglycerol, was synthesized and found to be potent (IC₅₀=100 nM) and selective versus other proteins and enzymes of the endocannabinoid system in vitro and active in vivo at reducing food intake in mice.

An X-ray-guided design approach led to the identification of a novel, balanced class of α-ethoxy-phenylpropionic acid-derived dual PPARα/γ agonists. The series shows a wide range of PPARα/γ ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.

We have optimized previously discovered benzoic acids 1, which are active as inhibitors of PTP1B and LMW-PTP, two protein tyrosine phosphatases that have emerged as attractive targets for the development of novel therapeutic agents for the treatment of diabetes, obesity, and cancer. Our efforts led to the identification of new and more potent analogues with appreciable selectivity toward human PTP1B and the IF1 isoform of human LMW-PTP.

Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.

Carnosine aryl derivatives as sequestering agents of RCS: Reactive carbonyl species (RCS) are cytotoxic mediators representing a novel drug target, as they are presumed to play a pathogenic role in several diseases. Carnosine is a selective RCS-sequestering agent, but is rapidly hydrolyzed by serum carnosinase. Herein we describe the in silico design, synthesis, and evaluation of a set of carnosine aryl derivatives.

Quality QSAR: A combination of docking calculations and a statistical approach toward Abl inhibitors resulted in a 3D QSAR model, the analysis of which led to the identification of ligand portions important for affinity. New compounds designed on the basis of the model were found to have very good affinity for the target, providing further validation of the model itself.

Drug–nanoparticle conjugates: The anticancer drug camptothecin (CPT) was covalently linked at the surface of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) via a linker, allowing drug release by cellular esterases. Nanoparticles were hierarchically built to achieve magnetically-enhanced drug delivery to human cancer cells and antiproliferative activity.

Antitumour activity was observed in a series of tricyclic compounds characterised by a 2-(1H-pyrrol-3-yl)-1,3,4-oxadiazole moiety with various substitutions. Their synthesis and antiproliferative activity toward a panel of human tumour cell lines is described. The most interesting compounds 1 c and 4 c were selected for further evaluation to elucidate their possible mechanism of action.

A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat and human adenosine receptors. Binding data demonstrates that some compounds could represent new tools suitable for in vivo studies in rat models of Parkinson's disease and for the design of new molecules with improved affinity and selectivity at human AA_2AR.

Wiley, Hoboken 2008. x+304 pp., hardcover $ 99.95.—ISBN 978-0-470-10705-8

Wiley-VCH, Weinheim 2008. xxv+624 pp., hardcover € 159.00.—ISBN 978-3-527-32051-6

Humana Press, Totowa 2008. xviii+396 pp., hardcover $ 129.00.—ISBN 978-1-934115-23-7

Humana Press, Totowa 2008. xi+382 pp., hardcover $ 99.50.—ISBN 978-1-58829-791-4