Photoredox Nucleophilic (Radio)fluorination of Alkoxyamines.

Herein, we report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C-H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity (Am) for (pre)clinical evaluation.

[18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid ß In Vivo.

We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36, a highly potent (hAß42 cell IC50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aß42 reduction in mouse and dog animal models.

Scaffold Hopping to Imidazo[1,2-a]pyrazin-8-one Positive Allosteric Modulators of Metabotropic Glutamate 2 Receptor.

Glutamate hyperfunction is implicated in multiple neurological and psychiatric diseases. Activation of the mGlu2 receptor results in reduced glutamate release and decreased excitability representing a promising novel therapeutic agent for the treatment of disorders such as epilepsy, schizophrenia, mood, anxiety, and other neuropsychiatric disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs from different chemical series. Herein, the discovery and optimization of a novel series of imidazopyrazinone mGlu2 PAMs are reported. This new scaffold originated from computational searching of fragment databases and comparison with our previously explored scaffolds. Optimization guided by our robust understanding of SAR from former series led to potent, selective, and brain-penetrant compounds.

Late-stage difluoromethylation: concepts, developments and perspective.

This review describes the recent advances made in difluoromethylation processes based on X-CF2H bond formation where X is C(sp), C(sp2), C(sp3), O, N or S, a field of research that has benefited from the invention of multiple difluoromethylation reagents. The last decade has witnessed an upsurge of metal-based methods that can transfer CF2H to C(sp2) sites both in stoichiometric and catalytic mode. Difluoromethylation of C(sp2)-H bond has also been accomplished through Minisci-type radical chemistry, a strategy best applied to heteroaromatics. Examples of electrophilic, nucleophilic, radical and cross-coupling methods have appeared to construct C(sp3)-CF2H bonds, but cases of stereoselective difluoromethylation are still limited. In this sub-field, an exciting departure is the precise site-selective installation of CF2H onto large biomolecules such as proteins. The formation of X-CF2H bond where X is oxygen, nitrogen or sulfur is conventionally achieved upon reaction with ClCF2H; more recently, numerous protocols have achieved X-H insertion with novel non-ozone depleting difluorocarbene reagents. All together, these advances have streamlined access to molecules of pharmaceutical relevance, and generated interest for process chemistry.

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.

Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders.

O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer's disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked N-acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein. Herein, we report the multifactorial optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-56. The human OGA X-ray crystal structure has been recently solved, but bacterial hydrolases are still widely used as structural homologues. For the first time, we reveal how a nonsaccharide series of inhibitors binds bacterial OGA and discuss the suitability of two different bacterial orthologues as surrogates for human OGA. These breakthroughs enabled structure-activity relationships to be understood and provided context and boundaries for the optimization of druglike properties.

[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.

Easy Access to Aliphatic Sulfonamides using Sulfamoyl Chlorides Under Visible Light Activation.

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due to their unique biological properties. Recently, several methods for the synthesis of aryl sulfonamides have been developed, but little effort has focused on developing one-step methodologies to access sulfonamides flanked by two alkyl groups. This protocol describes a practical and facile method for the net hydrosulfamoylation of electron-deficient alkenes using sulfamoyl chlorides as radical precursors under blue-light activation. This practical and cost-effective methodology is performed in the presence of the metal-free photocatalyst Eosin Y and uses light as a clean and traceless energy source. The procedure is scalable, displays a broad functional group tolerance, and can be applied for late-stage functionalization. All reagents used in this protocol are commercially available. Simple reaction set-up, the absence of work-up and easy purification, demonstrate the convenience of this protocol. The reaction is best applied to electron-deficient alkenes.

Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines.

Ammonium salts are used as phase-transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. This process, which highlights the ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery.

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.

Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under Visible Light Activation.

Sulfonyl chlorides are inexpensive reactants extensively explored for functionalization, but never considered for radical hydrosulfonylation of alkenes. Herein, we report that tris(trimethylsilyl)silane is an ideal hydrogen atom donor enabling highly effective photoredox-catalyzed hydrosulfonylation of electron-deficient alkenes with sulfonyl chlorides. To increase the generality of this transformation, polarity-reversal catalysis (PRC) was successfully implemented for alkenes bearing alkyl substituents. This late-stage functionalization method tolerates a remarkably wide range of functional groups, is operationally simple, scalable, and allows access to building blocks which are important for medicinal chemistry and drug discovery.

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu2 Receptor PAMs.

Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR2 PAMs.

Silyl Radical-Mediated Activation of Sulfamoyl Chlorides Enables Direct Access to Aliphatic Sulfonamides from Alkenes.

Single electron reduction is more challenging for sulfamoyl chlorides than sulfonyl chlorides. However, sulfamoyl and sulfonyl chlorides can be easily activated by Cl-atom abstraction by a silyl radical with similar rates. This latter mode of activation was therefore selected to access aliphatic sulfonamides, applying a single-step hydrosulfamoylation using inexpensive olefins, tris(trimethylsilyl)silane, and photocatalyst Eosin Y. This late-stage functionalization protocol generates molecules as complex as sulfonamide-containing cyclobutyl-spirooxindoles for direct use in medicinal chemistry.

Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aß Phagocytosis.

Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity toward sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, amyloid-ß (Aß), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aß peptide that is thought to cause AD.

Evaluation of a Series of ß-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Despite several years of research, only a handful of ß-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

mGluR2 positive allosteric modulators: an updated patent review (2013-2018).

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid.

A facile method for the regioselective hydrodifluoromethylation of alkenes is reported using difluoroacetic acid and phenyliodine(III) diacetate in tetrahydrofuran under visible-light activation. This metal-free approach stands out as it uses inexpensive reagents, does not require a photocatalyst, and displays broad functional group tolerance. The procedure is also operationally simple and scalable, and provides access in one step to high-value building blocks for application in medicinal chemistry.

Progress toward allosteric ligands of metabotropic glutamate 7 (mGlu7) receptor: 2008-present.

Metabotropic glutamate type 7 (mGlu7) receptor is a member of the group III family of mGlu receptors. It is widely distributed in the central nervous system (CNS) and is preferentially expressed on presynaptic nerve terminals where it is thought to play a critical role in modulating normal neuronal function and synaptic transmission, making it particularly relevant in neuropharmacology. The lack of small-molecule mGlu7 ligands with adequate potency, selectivity and drug-like properties has resulted in difficulties in the preclinical validation of mGlu7 modulation in disease models. In the last decade, allosteric modulators of mGlu7 receptors have emerged as valuable tools with good potency, selectivity and physicochemical properties to study and unleash the therapeutic potential of mGlu7 receptors. This review focusses on the medicinal chemistry of mGlu7 receptor allosteric ligands discovered since 2008.

Inhibition of the Alanine-Serine-Cysteine-1 Transporter by BMS-466442.

Experiment and modeling were combined to understand inhibition of the alanine-serine-cysteine-1 (asc1) transporter. The structure-activity relationship (SAR) was explored with synthesis of analogues of BMS-466442. Direct target interaction and binding site location between TM helices 6 and 10 were confirmed via site directed mutagenesis. Computational modeling suggested the inhibitor binds via competitive occupation of the orthosteric site while also blocking the movement of TM helices that are required for transport.