Bioisoteres for carboxylic acids: From ionized isosteres to novel unionized replacements.

Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery.

Identification of ß-Glucocerebrosidase Activators for Glucosylceramide hydrolysis.

Several novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have distinct chemotypes. Positive allosteric modulators bind to a site on GCase and induce conformational changes, but also induce an equilibrium state between monomer and dimer.

European Medicinal Chemistry Leaders in Industry (EMCL) - On the Status and Future of Medicinal Chemistry Research in Europe.

The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an SNAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

Photocatalytic Late-Stage Functionalization of Sulfonamides via Sulfonyl Radical Intermediates.

A plethora of drug molecules and agrochemicals contain the sulfonamide functional group. However, sulfonamides are seldom viewed as synthetically useful functional groups. To confront this limitation, a late-stage functionalization strategy is described, which allows sulfonamides to be converted to pivotal sulfonyl radical intermediates. This methodology exploits a metal-free photocatalytic approach to access radical chemistry, which is harnessed by combining pharmaceutically relevant sulfonamides with an assortment of alkene fragments. Additionally, the sulfinate anion can be readily obtained, further broadening the options for sulfonamide functionalization. Mechanistic studies suggest that energy-transfer catalysis (EnT) is in operation.

Exploiting Configurational Lability in Aza-Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides.

Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. We have addressed this by exploiting, for the first time, a feature of sulfonimidamides in which it is possible for tautomeric structures to also be enantiomeric. Such sulfonimidamides can readily generate prochiral ions, which we have exploited in an enantioselective alkylation process. Selectivity is achieved using a readily prepared bis-quaternized phase-transfer catalyst. The overall process establishes the capability of configurationally labile aza-sulfur species to be used in asymmetric catalysis.

Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches.

This perspective discusses the role of pregnane xenobiotic receptor (PXR) in drug discovery and the impact of its activation on CYP3A4 induction. The use of structural biology to reduce PXR activity on drug discovery projects has become more common in recent years. Analysis of this work highlights several important molecular interactions, and the resultant structural modifications to reduce PXR activity are summarized. The computational approaches undertaken to support the design of new drugs devoid of PXR activation potential are also discussed. Finally, the SAR of empirical design strategies to reduce PXR activity is reviewed, and the key SAR transformations are discussed and summarized. In conclusion, this perspective demonstrates that PXR activity can be greatly diminished or negated on active drug discovery projects with the knowledge now available. This perspective should be useful to anyone who seeks to reduce PXR activity on a drug discovery project.

Zenker's Diverticulum: Can Protocolised Measurements with Barium SWALLOW Predict Severity and Treatment Outcomes? The "Zen-Rad" Study.

Although barium swallow imaging is established in the investigation of Zenker's diverticulum (ZD), no agreed measurement protocol exists. We developed a protocol for measuring ZD dimensions and aimed to correlate measurements with symptoms and post-operative outcomes. This prospective study included patients with confirmed ZD who underwent flexible endoscopic septal division (FESD) between 2014 and 2018. ZD was confirmed on barium radiology with measurements reviewed by two consultant radiologists. Symptom severity pre- and post-FESD was measured using the Dysphagia, Regurgitation, Complications (DRC) scale. Regression analyses were conducted to identify dimensions associated with therapeutic success, defined as remission (DRC score ≤ 1) 6 months after index FESD. In total, 67 patients (mean age 74.3) were included. Interobserver reliability (intraclass correlation coefficients-ICCs) was greatest for pouch width (0.981) and pouch depth (0.934), but not oesophageal depth (0.018). Male gender (60.9%) was associated with larger pouch height (P = 0.008) and width (P = 0.004). A positive correlation was identified between baseline DRC score and pouch depth (ρ 0.326, P = 0.011), particularly the regurgitation subset score (ρ 0.330, P = 0.020). The index pouch depth was associated with FESD procedure time (rho 0.358, P = 0.041). Therapeutic success was achieved in 64.2% and was associated with shorter pouch height (median 14.5 mm vs. 19.0 mm, P = 0.030), pouch width (median 19.9 mm vs. 28.8 mm, P = 0.34) and cricopharyngeal length (median 20.2 mm vs. 26.3 mm, P = 0.036). ZD dimensions may be feasible and were evaluated using Barium radiology. Specific parameters appear to correlate with severity and post-FESD outcomes, which aid with pre-procedural planning.

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl-O-(tert-butyl)hydroxylamine, t-BuONSO.

Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.

Is post-transplant metabolic syndrome associated with pre-liver transplant visceral adipose tissue area?

BACKGROUND: Post-liver transplant metabolic syndrome (PTMS) is a significant independent risk factor for the development of cardiovascular disease. The impact of pre-transplant body composition on the risk of developing PTMS has not been evaluated and was the aim of this study. METHODS: Seventy-five consecutive adult patients listed for liver transplant were included in the analysis. Anthropometric and metabolic data were collected pre-transplant and at three months post-transplant. Metabolic syndrome was defined in accordance with international guidelines. Skeletal muscle area (SMA), visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were derived from computed tomography. RESULTS: Ten patients (13%) developed de novo PTMS by 3 months post-transplant. Patients who developed PTMS had higher pre-transplant body mass index (BMI) (P = 0.01), VAT (P = 0.001) and SAT (P = 0.008). Univariate logistic regression found that BMI, VAT and SAT were significant predictors for the development of PTMS. After stepwise multivariate analysis, only VAT remained a significant predictor (OR 1.02, 95%CI 1.01-1.04; P = 0.04). CONCLUSIONS: Higher pre-transplant VAT is independently associated with the development of metabolic syndrome three months post-transplant. Body composition analysis using cross-sectional imaging prior to liver transplant can assist with identifying patients at greatest risk for developing PTMS.

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides.

Sulfoximines and sulfonimidamides are promising compounds for medicinal and agrochemistry. As monoaza analogues of sulfones and sulfonamides, respectively, they combine good physicochemical properties, high stability, and the ability to build complexity from a three-dimensional core. However, a lack of quick and efficient methods to prepare these compounds has hindered their uptake in molecule discovery programmes. Herein, we describe a unified, one-pot approach to both sulfoximines and sulfonimidamides, which exploits the high electrophilicity of sulfinyl nitrenes. We generate these rare reactive intermediates from a novel sulfinylhydroxylamine (R-O-N=S=O) reagent through an N-O bond fragmentation process. Combining sulfinyl nitrenes with carbon and nitrogen nucleophiles enables the synthesis of sulfoximines and sulfonimidamides in a reaction time of just 15 min. Alkyl, (hetero)aryl, and alkenyl organometallic reagents can all be used as the first or second component in the reaction, while primary and secondary amines, and anilines, all react with high efficiency as the second nucleophile. The tolerance of the reaction to steric and electronic factors has allowed for the synthesis of the most diverse set of sulfoximines and sulfonimidamides yet described. Experimental and computational investigations support the intermediacy of sulfinyl nitrenes, with nitrene formation proceeding via a transient triplet intermediate before reaching a planar singlet species.

High-intensity interval training improves cardiorespiratory fitness in cancer patients and survivors: A meta-analysis.

OBJECTIVE: The primary objective of this systematic review and meta-analysis was to compare the effects of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) and usual care (UC) on cardiorespiratory fitness (peak V̇O2 ) in cancer patients and survivors. Secondary objectives were to compare the effects of HIIT versus MICT and UC on other cardiopulmonary exercise testing (CPET) indices. Safety and adherence to HIIT were also evaluated. METHODS: A systematic review and meta-analysis of controlled trials were undertaken using eligible studies from electronic database searching (inception-December 2019). Mean differences (MD) with 95% confidence intervals (CI) were compared and heterogeneity assessed using Cochran's Q and I2 statistic. RESULTS: Twelve eligible studies included 516 participants with post-intervention CPET data. No serious adverse events occurred. Adherence to HIIT ranged between 71.2% and 95.6%. HIIT had significantly higher peak V̇O2 compared with UC (MD = 2.11 ml kg-1  min-1 , 95% CI 0.75-3.47, p = .002). No significant difference was found between HIIT and MICT (MD = 2.03 ml kg-1  min-1 , 95%CI -0.75-4.83, p = .15). HIIT was more effective than UC to improve peak oxygen pulse (MD = 1.59 ml/beat, 95%CI 0.06-3.12, p = .04). CONCLUSIONS: Quantitative assessment of HIIT studies indicates good compliance, with a significant effect on peak V̇O2 and peak oxygen pulse compared with UC in cancer patients and survivors. HIIT demonstrates a comparable effect with MICT to improve peak V̇O2 .

Poor Cardiorespiratory Fitness Is a Risk Factor for Sepsis in Patients Awaiting Liver Transplantation.

BACKGROUND: Patients with advanced liver disease are at increased risk of infection and other complications. A significant proportion of patients also have poor fitness and low muscle mass. The primary aim of this study was to investigate if cardiorespiratory fitness and body composition are risk factors for sepsis and other complications of advanced liver disease. METHODS: Patients being listed for liver transplantation underwent cardiopulmonary exercise testing to determine ventilatory threshold (VT). Computed tomography was used to measure skeletal muscle and subcutaneous and visceral adipose tissue indexes. All unplanned hospital admissions, deaths or delistings before transplantation were recorded. RESULTS: Eighty-two patients (aged 55.1 [50.6-59.4] years, median (interquartile range); male 87%] achieved a median VT of 11.7 (9.7-13.4) mL·kg·min. Their median model of end-stage liver disease, incorporating serum sodium score was 18 (14-22); and 37 had hepatocellular carcinoma. There were 50 admissions in 31 patients; with 16 admissions for sepsis in 13 patients. Patients with sepsis had a significantly lower VT (sepsis, 9.5 [7.8-11.9]; no sepsis, 11.8 [10.5-13.8] mL·kg·min; P = 0.003]. No body composition variables correlated with sepsis, nor were there any significant associations between VT and unplanned admissions for other indications. Multivariate logistic regression demonstrated that VT was independently associated with a diagnosis of sepsis (P = 0.03). Poisson regression revealed that VT was a significant predictor for the number of septic episodes (P = 0.02); independent of age, model of end-stage liver disease, incorporating serum sodium score, hepatocellular carcinoma diagnosis, presence of ascites, and ß-blocker use. CONCLUSIONS: Poor cardiorespiratory fitness is an independent risk factor for the development of sepsis in advanced liver disease.

Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation.

The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts to identify agonists yielded catechol derivatives, mimicking dopamine, with suboptimal DMPK parameters and low selectivity over the D5 subtype. However, more recent efforts to identify ligands capable of activating the D1 receptor have made substantial progress with the identification of non-catechol agonists with suitable properties to progress to clinical studies. In addition, several research groups have identified positive allosteric modulators that offer new potential. Furthermore, structural studies have surprisingly uncovered two potential allosteric binding sites, the most characterized of which appears to be on intracellular loop 2 (ICL2). This review highlights the recent progress in the field, covering both orthosteric and allosteric modes of activation, discusses the elucidation of the allosteric binding sites, and summarizes the clinical development status of various compounds.

Neoadjuvant therapy reduces cardiopulmunary function in patients undegoing oesophagectomy.

Neoadjuvant therapy (NAT) for oesophageal cancer may reduce cardiopulmonary function, assessed by cardiopulmonary exercise testing (CPEX). Impaired cardiopulmonary function is associated with mortality following esophagectomy. We sought to assess the impact of NAT on cardiopulmonary function using CPEX and assessing the clinical relevance of any change in particular if changes were associated with post-operative morbidity. This was a prospective, cohort study of 40 patients in whom CPEX was performed before and after NAT. Thirty-eight patients underwent surgery and follow-up with perioperative outcomes measured. The primary variables derived from CPEX were the anaerobic threshold (AT) and peak oxygen uptake (V˙O2peak). There were significant reductions in the AT (pre-NAT: 12.4 ±â€¯3.0 vs. post-NAT 10.6 ±â€¯2.0 mL kg-1.min-1; p = 0.001). This reduction was also evident for V˙O2peak (pre-NAT: 16.6 ±â€¯3.6 vs. post-NAT 14.9 ±â€¯3.7 mL kg-1.min-1; p = 0.004). The relative reduction in V˙O2peak was greater in chemotherapy patients who developed any peri-operative morbidity (p = 0.04). For patients who underwent chemoradiotherapy, there was a significantly greater relative reduction in AT (p = 0.03) for those who encountered a respiratory complication. Cardiopulmonary function significantly declined as a result of NAT prior to oesophagectomy. The reduction in AT and V˙O2peak was similar in both the chemotherapy and chemoradiotherapy groups.

One-Pot, Three-Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N-Sulfinyltritylamine, TrNSO.

Sulfonimidamides are increasingly important molecules in medicinal chemistry and agrochemistry, but their preparation requires lengthy synthetic sequences, which has likely limited their use. We describe a one-pot de novo synthesis of sulfonimidamides from widely available organometallic reagents and amines. This convenient and efficient process uses a stable sulfinylamine reagent, N-sulfinyltritylamine (TrNSO), available in one step on 10 gram scale, as a linchpin. In contrast to classical approaches starting from thiols or their derivatives, our TrNSO-based approach facilitates the rapid assembly of the three reaction components into a variety of differentially substituted sulfonimidamides containing medicinally relevant moieties, including pyridines and indoles. Analogues of the sulfonamide-containing COX-2 inhibitor Celecoxib were prepared and evaluated.

The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7.

Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.

Regioselectivity and Mechanism of Synthesizing N-Substituted 2-Pyridones and 2-Substituted Pyridines via Metal-Free C-O and C-N Bond-Cleaving of Oxazoline[3,2-a]pyridiniums.

Novel intermediate oxazoline[3,2-a]pyridiniums were facilely prepared from 2-(2,2-dimethoxyethoxy)-pyridines via acid promoted intramolecular cyclization. Sequentially, the quaternary ammonium salts were treated with different nucleophiles for performing regioselective metal-free C-O and C-N bond-cleaving to afford prevalent heterocyclic structures of N-substituted pyridones and 2-substituted pyridines. The reaction mechanism and regioselectivity were then systematically explored by quantum chemistry calculations at B3LYP/6-31 g(d) level. The calculated free energy barrier of the reactions revealed that aniline and aliphatic amines (e.g., methylamine) prefer to attack C8 of intermediate 4a, affording N-substituted pyridones, while phenylmethanamine, 2-phenylethan-1-amine and 3-phenylpropan-1-amine favor to attack C2 of the intermediate to form 2-substituted pyridines. With the optimized geometries of the transition states, we found that the aromatic ring of the phenyl aliphatic amines may form cation-π interaction with the pyridinium of the intermediates, which could stabilize the transition states and facilitate the formation of 2-substituted pyridines.