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Nijmegen, Netherlands

De Koning H.P.,University of Glasgow | Gould M.K.,University of Glasgow | Sterk G.J.,Mercachem BV | Tenor H.,Nycomed GmbH | And 3 more authors.
Journal of Infectious Diseases | Year: 2012

The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets. © 2012 The Author. Source

Enders D.,RWTH Aachen | Del Signore G.,RWTH Aachen | Del Signore G.,Mercachem BV | Raabe G.,RWTH Aachen
Turkish Journal of Chemistry | Year: 2013

The asymmetric synthesis of α-(heteroaryl)alkylamines was accomplished by employing a diastereoselective nucleophilic 1,2-addition of lithiated aromatic heterocycles to aldehyde SAMP-hydrazones, followed by BH 3·THF or SmI2 promoted removal of the chiral auxiliary. The CBz or benzoyl-protected amines were obtained in good yields (40%-78%) and excellent enantiomeric excesses (ee = 88%-99%). The methodology can be applied to the synthesis of highly enantioenriched α-amino acids (ee = 90%-99%). © TÜBITAK. Source

Merkx R.,Netherlands Cancer Institute | De Bruin G.,Netherlands Cancer Institute | Kruithof A.,Netherlands Cancer Institute | Van Den Bergh T.,Mercachem BV | And 4 more authors.
Chemical Science | Year: 2013

We developed a scalable synthesis of γ-thiolysine starting straight from lysine. The application of γ-thiolysine was compared to δ-thiolysine in the chemical synthesis of K48 and K33 linked diubiquitin conjugates. Both γ- and δ-thiolysine were found to perform equally efficiently as handles for non-enzymatic ubiquitination. This journal is © 2013 The Royal Society of Chemistry. Source

Leenders R.,Mercachem BV | Heeres J.,Janssen Research Foundation | Vandenput D.,Mercachem BV | Guillemont J.,Johnson and Johnson Pharmaceutical Research and Development | Lewi P.,Janssen Research Foundation
Synthetic Communications | Year: 2011

Sterically hindered electron-deficient anilines are coupled to the 6-position of the purine core only when activated as their corresponding TFA-amide. The free anilines did not react under all conditions tested. After aqueous work-up, the TFA-group is lost. This procedure provides a new tool in the construction of purines functionalized with a sterically hindered electron-deficient aniline in the 6-position. Copyright © 2011 Taylor & Francis Group, LLC. Source

Kubas H.,Merz Pharmaceuticals GmbH | Meyer U.,Merz Pharmaceuticals GmbH | Hechenberger M.,Merz Pharmaceuticals GmbH | Klein K.-U.,Merz Pharmaceuticals GmbH | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis' AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development. © 2013 Elsevier Ltd. All rights reserved. Source

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