Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.

Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.

High-throughput purification of single compounds and libraries.

The need for increasing productivity in medicinal chemistry and associated improvements in automated synthesis technologies for compound library production during the past few years have resulted in a major challenge for compound purification technology and its organization. To meet this challenge, we have recently set up three full-service chromatography units with the aid of in-house engineers, different HPLC suppliers, and several companies specializing in custom laboratory automation technologies. Our goal was to combine high-throughput purification with the high attention to detail which would be afforded by a dedicated purification service. The resulting final purification laboratory can purify up to 1000 compounds/week in amounts ranging from 5 to 300 mg, whereas the two service intermediate purification units take 100 samples per week from 0.3 to 100 g. The technologies consist of normal-phase and reversed-phase chromatography, robotic fraction pooling and reformatting, a bottling system, an automated external solvent supply and removal system, and a customized, high-capacity freeze-dryer. All work processes are linked by an electronic sample registration and tracking system.

SynCar: an approach to automated synthesis.

The automation of all aspects of manual solution-phase synthesis into one integrated, efficient, and reliable system could be regarded as something of an unmet challenge in organic chemistry. The requirements for modern solution-phase libraries in mainstream drug discovery is typically 50-250 high-purity compounds on a 10-100-mg scale, whether for target class libraries or lead optimization, and short cycle time in combination with high capacity is critical. To achieve these goals, in a codevelopment between Aventis and Accelab GmbH, Kusterdingen, Germany, we designed a completely novel system of independent workstations connected by a shuttle transfer system produced by Montech, Derendingen, Switzerland. Seven modular workstations process four reactions on each shuttle in parallel, with the ability to perform synthesis (temperature control and liquid reagent handling), filtration, liquid-liquid extraction, evaporation, weighing, solid-phase extraction, and HPLC/MS analysis. The modular design enables the continuous loading of shuttles at any time, and each shuttle can have its own workflow. The design also allows easy expansion for future needs. The result is a combination of high flexibility and high throughput.