Diagnosing the decline in pharmaceutical R&D efficiency.

The past 60 years have seen huge advances in many of the scientific, technological and managerial factors that should tend to raise the efficiency of commercial drug research and development (RD). Yet the number of new drugs approved per billion US dollars spent on RD has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solutions to the problem of declining RD efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the number of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research-brute force' bias. Our aim is to provoke a more systematic analysis of the causes of the decline in RD efficiency.

A highly automated, polymer-assisted strategy for the preparation of 2-alkylthiobenzimidazoles and N,N'-dialkylbenzimidazolin-2-ones.

A multistep, polymer-assisted solution phase strategy for the highly automated (auto-PASP) synthesis of 2-alkylthiobenzimidazole and N,N'-dialkylbenzimidazolin-2-one libraries is presented. The approach incorporates in-line purification techniques to afford library products directly with high purities and is exemplified by the preparation of a 96-member 2-alkylthiobenzimidazoline library 1[1-12,1-8] and a 72-member N,N'-dialkylbenzimidazolin-2-one library 9[1-12,1-6].

Automated flow-through synthesis of heterocyclic thioethers.

The fully automated, sequential flow-through synthesis of a 44-member array of thioethers 10[1-4,1-11] employing a resin "capture and release" reactor column is described. The array incorporates four different heterocyclic scaffolds, and the synthesis was performed using a custom-built robotic synthesizer that is able to (i) load and regenerate the reactor column and (ii) array each product into a single vial using UV threshold detection. All the compounds were obtained in high yield (>75%) and excellent purity (>95%) without the need for further purification.

A fluorous-tagged, acid-labile protecting group for the synthesis of carboxamides and sulfonamides.

A new acid-labile, fluorous-tagged protecting group that facilitates the preparation of carboxamides and sulfonamides by parallel solution-phase synthesis is introduced. Its use is exemplified by the preparation of a 27-member library of biaryl sulfonamides and an 18-member library of biaryl carboxamides. Intermediates were purified by solid-phase extraction over reversed-phase fluorous silica gel to afford library members in high yields and purities (>95%) without the need for column chromatographic purification.

Fully automated polymer-assisted synthesis of 1,5-biaryl pyrazoles.

The polymer-assisted solution-phase (PASP) synthesis of a 192-member 2-D array of 1,5-biaryl pyrazoles 4[1-12,1-16] is reported. The synthesis was performed in a fully automated manner using a multiprobe top-filtration robot and incorporates a "catch and release" step to afford library compounds directly in high yield and purity.

A novel phase-switching protecting group for multi-step parallel solution phase synthesis.

A new phase-tag 1 which facilitates the parallel solution phase synthesis of carboxylic acids, esters, and carboxamides is reported. The new phase tag assists compound purification by enabling the selective resin capture of reaction products in either a reversible pH dependent manner (solid-phase extraction), or irreversibly in a Diels-Alder reaction.

Automated parallel, multi-step polymer-assisted solution phase (PASP) synthesis of substituted benzimidazole derivatives.

The automated polymer-assisted solution phase (PASP) synthesis of a 72 member library of 2-alkylthio-benzimidazoles 16 and benzimidazolin-2-ones 17 using commercially available robotic workstations is described. By incorporating both automated aqueous work-ups, in-line scavenging and 'catch and release' protocols the desired compounds were obtained directly in good yields and excellent purities without the need for conventional chromatographic purification. The synthesis described demonstrates how both manual and automated equipment may be utilised together to provide a versatile approach that facilitates parallel compound synthesis.

Polymer-assisted, multi-step solution phase synthesis and biological screening of histone deacetylase inhibitors.

The polymer-assisted solution phase synthesis (PASP) of an array of histone deacetylase (HDAc) inhibitors is described. HDAc inhibitors have considerable potential as new anti-proliferative agents. Selected compounds were shown to inhibit both human endothelial cell proliferation, and the formation of tubules (neovascularisation) in an in vitro model of angiogenesis.

Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia).

The commercially important antihyperglycemic agent Rosiglitazone 1(Avandia) has been prepared in high purity by a multi-step, polymer-assisted solution phase (PASP) synthesis without the need for the conventional chromatographic purification of any intermediates.

Fully automated multi-step solution phase synthesis using polymer supported reagents: preparation of histone deacetylase inhibitors.

The first fully automated multi-step polymer assisted solution phase (PASP) synthesis is described. An array of histone deacetylase (HDAc) inhibitors was prepared by an unattended 4-5 step sequence incorporating in-line 'catch and release' purification.

Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system.

This paper presents the synthesis of combinatorial libraries performed on a single-channel glass micro reactor under hydrodynamic flow control. The experiments were carried out in a non-well based micro chip and consisted of the preparation of libraries of pyrazoles by means of a Knorr reaction of 1,3-dicarbonyl compounds with hydrazines. The aim of this work is to investigate the capabilities of an automated micro reactor based system to synthesise sequentially multiple analogue reactions. Small slugs of reactants were introduced automatically by an autosampler in a serpentine-etched glass chip. The mobility of the reagents and products was achieved using hydrodynamic driven flow. Reaction slug dilution and UV slug detection took place at the outlet. A sample of the slug was analysed by using an on-line LC-UV-MS system. The degree of conversion was quantified using the UV signal and comparing with standards of starting materials and final products. After the LC-UV-MS analysis, the automated system proceeds to inject the slugs to carry out the next reaction programmed. The results suggest that the micro reactor system is capable of repeating the process of injection, mixing and reaction in an automated manner as many times as required.

Synthesis of a three-member array of cycloadducts in a glass microchip under pressure driven flow.

The synthesis of a series of cycloadduct products carried out in a glass microchip under pressure driven flow is presented. Initially, four different compounds were synthesized individually with conversions similar to those obtained in the corresponding batch macroscale reactions. Using identical experimental conditions for all four compounds, the results were highly predictable and reproducible, without the need for individual optimization. A multi-reaction experiment was then carried out in a single chip achieving the synthesis of a three-member array in a single run.

A Hantzsch synthesis of 2-aminothiazoles performed in a heated microreactor system.

This paper presents the first example known to the authors of a heated organic reaction performed on a glass microreactor under electro-osmotic flow control. The experiments consisted of the preparation of a series of 2-aminothiazoles by means of a Hantzsch reaction of ring-substituted 2-bromoacetophenones and 1-substituted-2-thioureas carried out in microchannels, with the aim of investigating the generic utility of the reactor in carrying out analogue reactions. The reactions were performed on T-design microchips etched into a thin borosilicate glass plate and sealed over with a thick borosilicate top plate containing reservoirs. The mobility of the reagents and products was achieved using electro-osmotic flow (EOF), with the driving voltages being generated by a computer-controlled power supply. During the experiments the T-shaped chip was heated at 70 C using a Peltier heater, aligned with the channels and the heat generated by this device was applied to the lower plate. The degree of conversion was quantified by LC-MS using UV detection by comparison with standard calibration curves for starting materials and final products. In all cases, conversions were found to be similar or greater than those found for equivalent macro scale batch syntheses, thus illustrating the potential of this heated microreactor system to generate a series of compounds which contain biologically active molecules.