187283-17-6Relevant articles and documents
Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach
Hoffer, Laurent,Voitovich, Yuliia V.,Raux, Brigitt,Carrasco, Kendall,Muller, Christophe,Fedorov, Aleksey Y.,Derviaux, Carine,Amouric, Agnès,Betzi, Stéphane,Horvath, Dragos,Varnek, Alexandre,Collette, Yves,Combes, Sébastien,Roche, Philippe,Morelli, Xavier
, p. 5719 - 5732 (2018)
Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.
XANTHINE DERIVATIVES AND USES THEREOF AS INHIBITORS OF BROMODOMAINS OF BET PROTEINS
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, (2019/05/22)
The present invention relates to a compound having the following formula (I): (I) wherein: - R is a (C1-C6)alkyl group;- R'' is preferably H;- Ar is a (C5-C12)arylene radical;- X1 is -C(=O)- or -SO2-; and- R' is chosen from the group consisting of possibly substituted (C1-C6)alkyl, heteroaryl, (C5-C12)aryl, and (hetero)cycloalkyl groups, or a pharmaceutically acceptable salt and/or tautomeric form thereof, or its racemates, diastereomers or enantiomers.
Structure-guided, single-point modifications in the phosphinic dipeptide structure yield highly potent and selective inhibitors of neutral aminopeptidases
Vassiliou, Stamatia,W?glarz-Tomczak, Ewelina,Berlicki,Pawe?czak, Ma?gorzata,Nocek, Bogus?aw,Mulligan, Rory,Joachimiak, Andrzej,Mucha, Artur
, p. 8140 - 8151 (2014/12/10)
Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor-enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1′-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1′ residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. Another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π-π stacking interaction between a pyridine ring and Tyr372.
