Practical electrochemical hydrogenation of nitriles at the nickel foam cathode.

We report a scalable hydrogenation method for nitriles based on cost-effective materials in a very simple two-electrode setup under galvanostatic conditions. All components are commercially and readily available. The method is very easy to conduct and applicable to a variety of nitrile substrates, leading exclusively to primary amine products in yields of up to 89% using an easy work-up protocol. Importantly, this method is readily transferable from the milligram scale in batch-type screening cells to the multi-gram scale in a flow-type electrolyser. The transfer to flow electrolysis enabled us to achieve a notable 20 g day-1 productivity of phenylethylamine at a geometric current density of 50 mA cm-2 in a flow-type electrolyser with 48 cm2 electrodes. It is noteworthy that this method is sustainable in terms of process safety and reusability of components.

Praziquantel - 50 Years of Research.

Investigations on praziquantel (PZQ) started fifty years ago by a cooperation between Bayer AG and Merck KGaA. Until today PZQ is the drug of choice for schistosomiasis in human medicine and used in many combinations with antinematode drugs in veterinary medicine. The Sm.TRPMPZQ , a Ca2+ -permeable transient receptor potential (TRP) channel, has been discovered as primary target of PZQ during the last decade. Furthermore, there is a short overview of routes of large-scale synthesis of racemic and pure (R)-PZQ. Until now racemic PZQ is used in veterinary and human medicine. In 2012 the Pediatric Praziquantel Consortium started PZQ chemistry and process development of pure (R)-PZQ for human application. It is hoped that (R)-PZQ will become available for pediatric use soon. The knowledge of the binding pocket of PZQ in Sm.TRPMPZQ allows to design synthesis of PZQ-derivatives of the next generation for a target-site directed screening. A similar screening should also be started for Fasciola hepatica TRPMPZQ .

Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates.

The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1µM) led to the most potent compound 27 (IC50: 0.038µM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.

Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa.

Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.

Halothiophene benzimidazoles as P1 surrogates of inhibitors of blood coagulation factor Xa.

Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor Xa were identified via screening of a compound library. The X-ray crystal structure of representative 3a bound to human fXa confirmed the S1 binding mode. Starting from 3a a series of halothiophene benzimidazoles was synthesized and investigated for their factor Xa inhibitory activity. This led to potent and selective achiral inhibitors against fXa such as compounds 9k and 9w.