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Pharmaceutical industry perspectives on flow chemocatalysis and biocatalysis
No full textIn response to a growing demand for more sustainable and cost-effective synthetic processes, the pharmaceutical industry is increasingly relying on continuous manufacturing as a valuable alternative to conventional batch processing. Particularly, flow processing may enable process intensification of chemocatalytic and biocatalytic transformations, both being of strategic importance on the design and production of active pharmaceutical ingredients. This review outlines the current status of flow chemocatalysis and biocatalysis within the pharmaceutical landscape. Furthermore, the trends and challenges that these technologies face are highlighted, based on recently disclosed applications from industry and innovative solutions from academia
Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QTc Prolongation Liability Determinations: A Pharma Perspective
No full textThe appropriate and efficient assessment of drug-induced clinical QTc prolongation (a surrogate marker of Torsades de Pointes arrhythmia) remains a concern of drug developers and regulators worldwide. Refined and validated over 15+ years, the nonclinical ICH S7B guidance describes two core assays (in vitro hERG/IKr current & in vivo QT studies) to assess the potential for delayed ventricular repolarization. Incorporating these assays early in candidate selection has lead to: i) a low prevalence of QTc prolonging drugs in clinical trials, and ii) no drugs have been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical findings still minimally influence ICH E14-based strategies for interpreting clinical QTc prolongation, and defining proarrhythmic risk.
In particular, the value of ICH S7B-based findings for candidates demonstrating minimal hERG/IKr block and minimal in vivo QTc prolongation at comparable clinical exposures (i.e., “double-negative nonclinical findings” are underestimated. Such reassuring nonclinical data has clear value assessing the risk of clinical QTc prolongation when clinical evaluation may be challenged by heart rate changes, exposure limitations, or safety considerations.
The time has come to meaningfully merge nonclinical and clinical approaches to provide a more comprehensive and integrated proarrhythmia risk assessment strategy that complements advances described in ICH E14 amendments to enable more flexible clinical QTc risk assessments. Adoption of a truly integrative nonclinical/clinical risk assessment in the context of the low prevalence of QTc prolonging drugs would positively impact regulatory science, relieve the burden of extensive QTc monitoring, and streamline drug development
The upside of being a digital pharma player
No full textWe investigated the state of artificial intelligence (AI) in pharmaceutical research and development (R&D) and outline here a risk and reward perspective regarding digital R&D. Given the novelty of the research area, a combined qualitative and quantitative research method was chosen, including the analysis of annual company reports, investor relations information, patent applications, and scientific publications of 21 pharmaceutical companies for the years 2014 to 2019. As a result, we can confirm that the industry is in an ‘early mature’ phase of using AI in R&D. Furthermore, we can demonstrate that, despite the efforts that need to be managed, recent developments in the industry indicate that it is worthwhile to invest to become a ‘digital pharma player’
A Randomized Controlled Trial of a Farnesoid X Receptor Agonist, Tropifexor, in Patients with Primary Bile Acid Diarrhea
No full textBackground: In primary bile acid diarrhoea (PBAD), feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired.
Aims: To evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non-bile acid FXR agonist, in patients with PBAD.
Methods: In this double-blind, multicentre, randomised, cross-over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of 2 treatment periods. Primary objectives included tropifexor effect on safety, tolerability, stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers, and gastrointestinal transit.
Results: Twenty patients (tropifexor 60 µg/placebo [N=10]; placebo/tropifexor 60 µg [N=10]) were enrolled. Adverse event rates were lower with tropifexor versus placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post-dose on Days 1 and 12. At Day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P=0.032) and exposure (36%, P=0.005). Moreover, tropifexor showed significant increase in ascending colonic half-emptying time (P=0.036).
Conclusions: Tropifexor 60 µg once daily had an acceptable safety and tolerability profile. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with PBAD
Discovery And Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with Salt-Bridge for Improvement of Oral Exposure
No full textG-protein-coupled receptor SUCNR1 (succinate receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation
Immune cell landscaping reveals a protective role for Tregs during kidney injury and fibrosis
No full textAcute kidney injury (AKI) and chronic kidney diseases (CKD) are associated with high mortality and morbidity in hospitalized patients. Although the underlying mechanisms determining the transition from acute to irreversible chronic injury are not well understood, immune mediated inflammatory processes are critical in renal injury. We have performed a comparison of two mouse models leading to either kidney regeneration or fibrosis, to better characterize the cellular and molecular events leading to both outcomes. Global gene expression profiling and histological analysis revealed a major upregulation of immune system related pathways during fibrosis. Further unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed that tissue resident macrophages and T cells were major altered populations. In fibrotic kidneys, there was a marked increase in tissue resident IL33R+ and IL2Ra+ regulatory T cells (Tregs). Indeed, prophylactic expansion of this population resulted in protection from kidney injury and fibrosis. Transcriptional profiling of Tregs showed a differential up-regulation of regenerative and pro-angiogenic set of genes in the regeneration model, whereas they expressed markers of hyper activation and fibrosis in the fibrosis model. This suggests that Tregs could exert different functions in the same tissue, dictated by environmental cues. Overall, we have provided a detailed cellular and molecular characterization of murine kidneys after injury and identified key changes in immune cell populations during fibrosis development
N2Phos. An easily made, highly effective ligand designed for ppm level Pd-catalyzed Suzuki-Miyaura cross couplings in water
No full textA new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/hetroaryl bromides is amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000-2500 ppm or 0.10-0.25 mol %). Density funtional theory calculations suggest that greater steric congestion in N2Phos induces increased steric crowding around the Pd center, preventing formation of a 2:1 ligand-Pd complex found with EvanPhos (and less bulky ligands) that could slow oxidative addition to aryl chlorides
Antihypertensive drug treatment and serum ACE2 levels
No full textThe current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with major respiratory failure where the old and those with an underlying chronic disease are at highest risk of mortality1. Several factors have been proposed that may be underlying the higher mortality rates in these high-risk groups. The most frequent comorbidities associated with COVID-19 related mortality are clinical hypertension and type 2 diabetes (T2D)2,3. Although lower survival can simply be attributed to the frailty of this population, it has been suggested that administration of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may affect the susceptibility to COVID-19 related outcomes by upregulating ACE24. It is well known that ACE2 is the cellular receptor that COVID-19 and other SARS coronaviruses bind to for entering the host cell5
ACE2 levels are altered in comorbidities linked to severe outcome in COVID-19 Subtitle: ACE2 serum levels are increased in metabolic disease
No full textImportance Recent reports have shown that hypertension, kidney disease, obesity, type 2 diabetes (T2D) and cardiovascular disease are the among the most common comorbidities associated with severe outcome from the current coronavirus disease 2019 (COVID-19), which may be related to the frailty and/or medication use of this patient population. However, it´s possible that individuals with these comorbidities have altered serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2.
Objective To examine if individuals that manifest with comorbidities associated with severe outcome from COVID-19 have altered circulating levels of ACE2.
Design, Setting, and Participants A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) investigated with respect to hypertension, T2D, obesity or CHD.
Main Outcomes and Measures Associations of serum levels of ACE2 were examined in the AGES-RS study population according to body mass index (BMI) (kg/m2), hypertension, type 2 diabetes (T2D), CHD and other relevant phenotypes.
Results ACE2 levels were significantly elevated in the sera from smokers and individuals suffering from T2D and/or obesity, while males had reduced ACE2 levels
Conclusions and Relevance ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as a circulating biomarker for severity of outcome in COVID-19