Karawajczyk A.,Taros Chemicals GmbH and Co. KG |
Giordanetto F.,Taros Chemicals GmbH and Co. KG |
Benningshof J.,Mercachem |
Hamza D.,Sygnature Discovery |
And 7 more authors.
Drug Discovery Today | Year: 2015
High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes. Source
Veerman J.,Mercachem |
Van Den Bergh T.,Mercachem |
Orrling K.M.,VU University Amsterdam |
Jansen C.,VU University Amsterdam |
And 11 more authors.
Bioorganic and Medicinal Chemistry | Year: 2016
Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4 nM) and TbrPDEB2 (IC50: 3 nM) (J. Infect. Dis. 2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease. © 2016 Elsevier Ltd. All rights reserved. Source
Molenveld P.,Mercachem |
Bouzanne Des Mazery R.,Mercachem |
Sterk G.J.,Mercachem |
Storcken R.P.M.,Mercachem |
And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015
All diastereoisomeric decahydroquinoxalines representing conformationally restricted analogs of κ agonists U-50,488 and GR-89,696 have been prepared. Cis/trans configured compound 7 is by far the highest binding diastereoisomer with a Ki of 0.35 nM. Racemates 4, 6, and 7 were separated into enantiomers. (+)-(4aR,5S,8aS)-Configured enantiomer 7b was identified as a high affinity (Ki = 0.25 nM) κ ligand with high selectivity over μ and δ receptors. It acts as full agonist with an EC50 value of 2.0 nM in the [35S]GTPγS assay, while enantiomer 7a showed an EC50 value of 1000 nM. © 2015 Elsevier Ltd. All rights reserved. Source
Padwal J.D.,Leiden University |
Filippov D.V.,Leiden University |
Narhe B.D.,Leiden University |
Aertssen S.,Mercachem |
And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015
A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp3-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared. © 2015 Elsevier Ltd. All rights reserved. Source
Zwanenburg B.,Radboud University Nijmegen |
Regeling H.,Mercachem |
van Tilburg-Joukema C.W.,Mercachem |
van Oss B.,Mercachem |
And 3 more authors.
European Journal of Organic Chemistry | Year: 2016
Strigolactones (SLs) constitute an important new class of plant hormones. Their isolation from natural resources, such as root exudates, is laborious and difficult. Therefore, synthetic SLs are needed to discover their (biological) properties. Such syntheses involve many steps. When repeating a published procedure for the synthesis of orobanchol, we noticed that the structure of the synthesized material was ambiguous. This structure was secured by means of X-ray analysis. An essential step in the synthesis, namely an allylic oxidation of the ABC scaffold, was significantly improved by using Pd/C and tert-butyl hydroperoxide (Corey's method). The second issue deals with the structure of the four stereoisomers of 5-deoxystrigol. The stereochemistry of these compounds was based on the use of Welzel's empirical rules for CD spectra. By means of X-ray analysis the stereochemistry of one of the stereoisomers was established unambiguously, thereby securing the configuration of all four isomers. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source