Electrochemical C-O and C-N Arylation using Alternating Polarity in Flow for Compound Libraries.

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure-activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C-X arylation (X = NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across > 30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C-X arylation compound libraries using flow electrochemistry.

Late-Stage C(sp2)-C(sp3) Diversification via Nickel Oxidative Addition Complexes.

Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp2)-C(sp3) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery.

The intriguing role of USP30 inhibitors as deubiquitinating enzymes from the patent literature since 2013.

INTRODUCTION: Ubiquitin specific peptidase 30 (USP30) is a mitochondrial deubiquitinase that antagonizes ubiquitination-mediated mitophagy of damaged or impaired mitochondria driven by the activity of PARK2/Parkin ubiquitin ligase and PINK1 protein kinase. Researchers have related low levels of USP30 to enhanced mitophagy and therefore have been pursuing mitophagy activation utilizing USP30 inhibitors as an alternative approach to target neurodegenerative disorders and other human diseases associated with defective mitophagy. AREAS COVERED: This review covers the research and patent literature on the discovery and development of USP30 inhibitors since 2013. EXPERT OPINION: Strategies toward mitophagy activation utilizing small-molecule inhibitors of USP30 have emerged as alternative pathways for the potential treatment of many human diseases. Research efforts have led to identifying potent and selective small-molecule USP30 inhibitors. Most small-molecule USP30 inhibitors share a common N-cyano motif that binds covalently to the target. Non-covalently binding inhibitors have recently been disclosed as well. Lead compounds exhibit satisfactory inhibitory activities and are currently in preclinical development. Regrettably, complete pharmacological characterization and in vivo evaluation to validate and prove the therapeutic potential is lacking. Target validation could pave the way for discovering and developing USP30 inhibitors that could ultimately lead to marketed drugs.

O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer's disease and related tauopathies: analysis of the patent literature.

Introduction: O-GlcNAcylation is a highly abundant post-translational modification of multiple proteins, including the microtubule-binding protein tau, governed by just two enzymes' concerted action O-GlcNAc transferase OGT and the hydrolase OGA. It is an approach to reduce abnormal tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) and related tauopathies based on the ability of O-GlcNAcylation competing with tau phosphorylation, thus minimizing aggregation. The preclinical validation confirmed OGA inhibitors' efficacy in different transgenic tau mice models. Only three other OGA inhibitors have advanced into clinical trials thus far.Areas covered: 2008-2020 patent literature on OGA inhibitors.Expert opinion: Neurodegenerative disorders and AD specifically represent an enormous challenge since no effective treatments are available. Promising preclinical data has prompted considerable interest in searching for OGA inhibitors as a potential treatment for neurodegenerative disorders. Efforts from different companies have yielded a diverse set of chemotypes. OGA is a highly ubiquitous enzyme with many client proteins, generated data confirms a promising benign profile for OGA inhibition in healthy volunteers. Additionally, OGA PET tracers' existence will be critical for proper dose selection for future PoC Phase II studies, which will proof the true potential of OGA inhibition for the treatment of AD and other tauopathies.

[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.

We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

Repurposing High-Throughput Image Assays Enables Biological Activity Prediction for Drug Discovery.

In both academia and the pharmaceutical industry, large-scale assays for drug discovery are expensive and often impractical, particularly for the increasingly important physiologically relevant model systems that require primary cells, organoids, whole organisms, or expensive or rare reagents. We hypothesized that data from a single high-throughput imaging assay can be repurposed to predict the biological activity of compounds in other assays, even those targeting alternate pathways or biological processes. Indeed, quantitative information extracted from a three-channel microscopy-based screen for glucocorticoid receptor translocation was able to predict assay-specific biological activity in two ongoing drug discovery projects. In these projects, repurposing increased hit rates by 50- to 250-fold over that of the initial project assays while increasing the chemical structure diversity of the hits. Our results suggest that data from high-content screens are a rich source of information that can be used to predict and replace customized biological assays.

Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present).

INTRODUCTION: The cyclic nucleotides cAMP and cGMP are ubiquitous intracellular second messengers regulating a large variety of biological processes. The intracellular concentration of these biologically relevant molecules is modulated by the activity of phosphodiesterases (PDEs), a class of enzymes that is grouped in 11 families. The expression of PDEs is tissue- and cell-specific allowing spatiotemporal integration of multiple signaling cascades. PDE2A is a dual substrate enzyme and is expressed in both the periphery and in the central nervous system, however its expression is highest in the brain, where it is mainly localized in the cortex, hippocampus, and striatum. This suggests that this enzyme may regulate intraneuronal cGMP and cAMP levels in brain areas involved in emotion, perception, concentration, learning and memory. AREAS COVERED: This review covers the patent applications published between January 2010 and February 2016 on phosphodiesterase 2A inhibitors. EXPERT OPINION: Recent publications in the literature and in filed patent applications demonstrate the interest of pharmaceutical companies for PDE2A. This has increased the insights of its possible therapeutic role but the few clinical trials were terminated. Based on the ongoing interest in the field it is likely that new clinical trials can be expected and will unravel the therapeutic potential of PDE2A inhibition.

Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors.

A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.

Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 µM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.

The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.