Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

RG7774 (Vicasinabin), an orally bioavailable cannabinoid receptor 2 (CB2R) agonist, decreases retinal vascular permeability, leukocyte adhesion, and ocular inflammation in animal models.

Introduction: Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents.

Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry.

Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon-carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners.

sp -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp -rich molecules.

Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning.

Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, the chemical complexity of drug molecules often makes late-stage diversification challenging. To address this problem, a late-stage functionalization platform based on geometric deep learning and high-throughput reaction screening was developed.

Identifying opportunities for late-stage C-H alkylation with high-throughput experimentation and in silico reaction screening.

Enhancing the properties of advanced drug candidates is aided by the direct incorporation of specific chemical groups, avoiding the need to construct the entire compound from the ground up. Nevertheless, their chemical intricacy often poses challenges in predicting reactivity for C-H activation reactions and planning their synthesis. We adopted a reaction screening approach that combines high-throughput experimentation (HTE) at a nanomolar scale with computational graph neural networks (GNNs).

Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions.

mRNA LNPs can experience a decline in activity over short periods (ranging from weeks to months). As a result, they require frozen storage and transportation conditions to maintain their full functionality when utilized. Currently approved commercially available mRNA LNP vaccines also necessitate frozen storage and supply chain management.

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties.

Antisense-oligonucleotides (ASOs) are a promising drug modality for the treatment of neurological disorders, but the currently established route of administration intrathecal delivery is a major limitation to its broader clinical application. An attractive alternative is the conjugation of the ASO to an antibody that facilitates access to the central nervous system (CNS) after peripheral application and target engagement at the blood-brain barrier, followed by transcytosis. Here, we show that the diligent conjugate design of Brainshuttle-ASO conjugates is the key to generating promising delivery vehicles and thereby establishing design principles to create optimized molecules with drug-like properties.

Rapid F- and F-Difluoromethylation through Desulfurative Fluorination of Transient N-, O-, and C-Linked Dithioles.

The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O-H, N-H and C-H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride.

Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner.

Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a).

Quaternary Ammonium Trifluoromethoxide Salts as Stable Sources of Nucleophilic OCF.

The reaction of nucleophilic tertiary amines with trifluoromethyl and pentafluoroethyl methyl ethers provides quaternary ammonium trifluoromethoxide (NROCF) and pentafluoroethoxide (NROCFCF) salts, respectively, in good yields. The new trifluoromethoxide salts disclosed herein are uniquely stable for extended periods of time in both the solid state and in solution, which complements contemporary reagents. Here we describe the preparation of a range of NROCF salts, their long-term stability, and utility in substitution reactions.

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride.

Herein we report the mild and rapid fluorodesulfurization of thionoesters using only silver(I) fluoride. This reaction demonstrates excellent functional group tolerance and complements existing strategies for difluoroalkyl ether synthesis, which rely on toxic and often dangerous reagents that demonstrate limited functional group compatibility. We additionally report the translation of this finding to the production of F-labelled difluoroalkyl ethers using fluoride-derived [ F]AgF.

Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice.

DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS.

Modulation of Pharmacologically Relevant Properties of Piperidine Derivatives by Functional Groups in an Equatorial or Axial β-Position to the Amino Group.

Thirteen epimeric pairs of 5-substituted N-piperonyl-3-phenylpiperidine derivatives were synthesized in order to explore the stereospecific modulation of basicity, lipophilicity, aqueous solubility, and membrane permeation by functional groups in equatorial or axial positions beta to the amine unit. While this comprehensive data set provides enhanced insight into multiple factors that affect basicity and lipophilicity, it fills an important knowledge gap, providing a frame of reference for the property-based design of bioactive compounds. Impacts on amine basicity are very pronounced for the β-equatorial functional groups and parallel basicity-lowering effects known for acyclic amine derivatives.

F-Branched-Chain Amino Acids: Structure-Activity Relationships and PET Imaging Potential.

The large, neutral L-type amino acid transporters (LAT1-LAT4) are sodium-independent transporters that are widely distributed throughout the body. LAT expression levels are increased in many types of cancer, and their expression increases as cancers progress, leading to high expression levels in high-grade tumors and metastases. Because of the key role and overexpression of LAT in many types of cancer, radiolabeled LAT substrates are promising candidates for nuclear imaging of malignancies that are not well revealed by conventional radiotracers.

Synthesis of acyl fluorides via photocatalytic fluorination of aldehydic C-H bonds.

Acyl fluorides are versatile acylating agents owing to their unique stability. Their synthesis, however, can present challenges and is typically accomplished through deoxyfluorination of carboxylic acids. Here, we demonstrate that acyl fluorides can be prepared directly from aldehydes via a C(sp)-H fluorination reaction involving the inexpensive photocatalyst sodium decatungstate and electrophilic fluorinating agent N-fluorobenzenesulfonimide.

Site-Selective, Late-Stage C-H F-Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging.

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [ F]-N-fluorobenzenesulfonimide effects site-selective F-fluorination at the branched position in leucine residues in unprotected and unaltered peptides.

Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives.

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug p, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp)-H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent -fluorobenzenesulfonimide.

2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.

Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold.

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.

Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds.

F-Fluorination of Unactivated C-H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological Positron Emission Tomography Imaging Agents.

A mild and selective photocatalytic C-H F-fluorination reaction has been developed that provides direct access to F-fluorinated amino acids. The biodistribution and uptake of three F-labeled leucine analogues via LAT1 mediated transport in several cancer cell lines is reported. Positron emission tomography imaging of mice bearing PC3 (prostate) or U87 (glioma) xenografts using 5-[F]-fluorohomoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strategy for rapid tracer discovery for oncology.

Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions.

A Convenient Late-Stage Fluorination of Pyridylic C-H Bonds with N-Fluorobenzenesulfonimide.

Pyridine features prominently in pharmaceuticals and drug leads, and methods to selectively manipulate pyridine basicity or metabolic stability are highly sought after. A robust, metal-free direct fluorination of unactivated pyridylic C-H bonds was developed. This convenient reaction shows high functional-group tolerance and offers complimentary selectivity to existing C-H fluorination strategies.

Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2).

A series of cyclopenta[c]pyridine aldosterone synthase (AS) inhibitors were conveniently accessed using batch or continuous flow Kondrat'eva reactions. Preparation of the analogous cyclohexa[c]pyridines led to the identification of a potent and more selective AS inhibitor. The structure-activity-relationship (SAR) in this new series was rationalized using binding mode models in the crystal structure of AS.