Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.

Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

Realisation of small molecule libraries based on frameworks distantly related to natural products.

The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.

A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production.

A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study. From a single starting material, topologically diverse scaffolds for library synthesis can be generated and decorated in a few steps. The methodology was used to produce a library of 490 compounds within the European Lead Factory (ELF) Consortium.

Mild and chemoselective lactone ring-opening with (TMS)ONa. Mechanistic studies and application to sweroside derivatives.

Mild and chemoselective opening of lactones with sodium trimethylsilanolate in high yields and aprotic solvents is described. Kinetic studies demonstrate that the B(Ac)2 mechanistic pathway is followed. Nucleophilic attack of silanolate onto the carbonyl of the lactone moiety is the rate-determining step. NaOH present as an impurity accelerates the reaction. The method was further applied to the base-sensitive and stable lactones derived from highly functionalized iridoid derivatives.

Affinity selection mass spectrometry speeding drug discovery.

Affinity selection mass spectrometry (AS-MS) has gained momentum in drug discovery. This review summarizes how this technology has slowly risen as a new paradigm in hit identification and its potential synergy with DNA encoded library technology. It presents an overview of the recent results on challenging targets and perspectives on new areas of research, such as RNA targeting with small molecules. The versatility of the approach is illustrated and strategic drivers discussed in terms of the experience of a small-medium CRO and a big pharma organization.

Incorporation of a 3-(2,2,2-trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities.

In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 µM. The most promising compounds (82 and 84) showed significant IC50 values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.