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In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Biocatalysis is a highly valued enabling technology for pharmaceutical research and development as it can unlock synthetic routes to complex chiral motifs with unparalleled selectivity and efficiency. This perspective aims to review recent advances in the pharmaceutical implementation of biocatalysis across early and late-stage development with a focus on the implementation of processes for preparative-scale syntheses., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Imine reductases (IREDs) catalyze the asymmetric reduction of cyclic imines, but also in some cases the coupling of ketones and amines to form secondary amine products in an enzyme-catalyzed reductive amination (RedAm) reaction. Enzymatic RedAm reactions have typically used small hydrophobic amines, but many interesting pharmaceutical targets require that larger amines be used in these coupling reactions. Following the identification of IR77 from Ensifer adhaerens as a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine, we have characterized the ability of this enzyme to catalyze couplings with larger bicyclic amines such as isoindoline and octahydrocyclopenta( c )pyrrole. By comparing the activity of IR77 with reductions using sodium cyanoborohydride in water, it was shown that, while the coupling of cyclohexanone and pyrrolidine involved at least some element of reductive amination, the amination with the larger amines likely occurred ex situ, with the imine recruited from solution for enzyme reduction. The structure of IR77 was determined, and using this as a basis, structure-guided mutagenesis, coupled with point mutations selecting improving amino acid sites suggested by other groups, permitted the identification of a mutant A208N with improved activity for amine product formation. Improvements in conversion were attributed to greater enzyme stability as revealed by X-ray crystallography and nano differential scanning fluorimetry. The mutant IR77-A208N was applied to the preparative scale amination of cyclohexanone at 50 mM concentration, with 1.2 equiv of three larger amines, in isolated yields of up to 93%., Competing Interests: The authors declare the following competing financial interest(s): Mark Petchey is currently a Postdoctoral Researcher at AstraZeneca R&D Gothenburg., (© 2023 The Authors. Published by American Chemical Society.)

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 ( 23 ). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23 , a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

Objectives: Prescription opioid use disorder (POUD) is an established public health crisis in many countries, and current evidence indicates it is a growing problem in Europe. Many specialists play a role, including pain and addiction medicine specialists, in the diagnosis and management of POUD, but neither group can fully address these patients' needs alone. The purpose of this consensus process was to bring together experts from pain and addiction medicine to examine the positions of both specialties., Methods: In all, 13 international pain medicine, addiction medicine, and addiction psychiatry experts convened a meeting to formulate a set of consensus statements on the diagnosis and management of POUD. The statements were further refined by a wider group of 22 European expert clinicians. At a second meeting of all 35 participants, a set of controversy statements was also developed to recognize some of the key areas of divergent opinion., Results/conclusions: There was a high level of agreement between pain and addiction specialists. Key themes that emerged were the need to strengthen interdisciplinary communication, a desire for greater education and training for clinicians in both specialties, and mutual acknowledgment of the importance of multidisciplinary management of POUD. The blurred line between poorly managed pain and POUD was also a subject of much discussion, reflecting the difficulties in defining and diagnosing this complex condition.

Ene-reductases (EREDs) catalyze the reduction of electron-deficient C═C bonds. Herein, we report the first example of ERED-catalyzed net reduction of C═C bonds of enimines (α,β-unsaturated imines). Preliminary studies suggest their hydrolyzed ring-open ω-amino enones are the likely substrates for this step. When combined with imine reductase (IRED)-mediated C═N reduction, the result is an efficient telescoped sequence for the preparation of diastereomerically enriched 2-substituted saturated amine heterocycles.

Carboxylic acid reductases (CARs) are an emerging biocatalyst platform for the synthesis of a diverse array of aldehydes from carboxylic acids, operating chemoselectively and under mild aqueous conditions. As such, there is growing interest in the industrial application of these enzymes, both for the synthesis of aldehyde end-products, which are particularly prevalent in the flavor and fragrance industries, and aldehyde intermediates in multi-enzyme cascades. This perspective aims to review recent developments in the applications of CARs with a focus on the challenges and considerations involved in their implementation, as well as potential solutions with a view to increased industrial utility., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Synthesis of the chiral amine moiety is a key challenge for synthetic organic chemistry due to its prevalence in many biologically active molecules. Imine reductase and amine oxidase enzymes have enabled the biocatalytic synthesis of a host of chiral amine compounds. In this chapter, procedures for the synthesis of chiral amines using imine reductases (IREDs), the recently discovered IRED homologues reductive aminases, and amine oxidases (AOs) are described. Amine oxidases have been the subject of mutagenesis approaches for improvement of substrate scope. The high-throughput screening method for determining active variants in amine oxidase libraries is illustrated. Finally, in an approach which takes inspiration from nature, many enzymes can be combined with each other in cascade reactions. The incorporation of imine reductase and monoamine oxidase biocatalysts into several cascade reactions, both in vitro and in vivo (where the approach moves toward synthetic biology), is reported., (© 2018 Elsevier Inc. All rights reserved.)

Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of (R)- and (S)-5-methyl-6,7-dihydro-5H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) that can catalyse the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalysing imine formation as well as reduction. Crystal structures of AspRedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient (R)-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover numbers of up to 32,000 and space time yields up to 3.73 g l -1  d -1 .

Imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines. The development of bioinformatics tools and searchable databases has led to the identification of a diverse range of new IRED biocatalysts that have been characterised and employed in different synthetic processes. This review describes the latest developments in the structural and mechanistic aspects of IREDs, together with synthetic applications of these enzymes, and identifies ongoing and future challenges in the field., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Complications following snake bites are not common in France. We report the case of a bilateral pulmonary embolism following a viper envenomation in France.A healthy 72-year-old female presented with a lower limb hematoma following a viper bite. She was admitted at the hospital 2 days later and received low-molecular-weight heparin because of bed rest. Seven days later, she complained of thoracic pain and respiratory failure, and a bilateral pulmonary was diagnosed, without biological sign of neither disseminated intravascular coagulation nor coagulation trouble. Repeated lower limbs Doppler ultrasound were normal.This case is particularly interesting because it is only the 7th reported case of pulmonary embolism following a snake envenomation; moreover, it happened in France where poisonous snakes are very rare.Several hypotheses have been made to explain this late localized coagulopathy: an increased level of unstable fibrin produced by thrombin-like glycoproteins from the venom is one of them.

HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity. Twenty-nine HIV1-infected patients (average 12 years of infection, nadir of CD4 210/mm, including 7 patients with a history of opportunistic infection) with a biopsy-proven or likely HIVOP have been followed up for an average of 6.1 years. Modes of revelation of the HIVOP were: cytolysis and/or cholestasis (60%), occult (14%) or symptomatic (37%) portal hypertension (esophageal varices 17%, ascites 10%, cytopenia 10%), or fortuitous (8%). Hypoalbuminemia (≤35 g/L) was present in (31%), thrombocytopenia (<150,000 platelets) in 52% and prothrombin rate <70% in 10%. Esophageal varices were detected in 71%. Thrombophilia was present in 23 patients (80%): in head, protein S deficiency (87%). MRI showed in 82% at least 1 morphological abnormality. The average value of the liver stiffness by Fibroscan was 8.3 kPa. During follow-up, there was no radiological improvement, 15 (52%) patients presented with variceal hemorrhage, 10 patients (34%) ascites, 10 (34%) portal vein thrombosis, 7 (24%) an iron deficiency, and 2 (7%) with a protein-losing enteropathy, including 14 patients (48%) with several events. Four patients (14%) were transplanted, 1 (25%) recurred the HIVOP on the graft, and 1 patient is waiting for a transplant. HIVOP is a severe disease associated with high morbidity related to symptomatic portal hypertension, which occurred in 50% and required liver transplantation in 14%.

Nocardia are Gram-positive filamentous bacteria responsible for infections ranging from opportunistic life-threatening disseminated diseases to chronic skin and soft-tissue infections.Even if virtually all organs can be infected, articular involvement is rare. Therefore, we report 3 recent cases and performed a literature review of cases of Nocardia arthritis in order to describe clinical features, therapeutic challenges, and outcome of these patients.Among 34 patients (31 in the literature plus our 3 cases), 21 (62%) were due to hematogenous dissemination, 9 (26%) were due to direct bacterial inoculation through the skin, and in 4 cases, the mechanism of infection was unknown. Four out of these 34 cases occurred on prosthetic joints.Whereas hematogenous infections mostly occurred in immunocompromised hosts (17 of 21, 81%), direct inoculation was mostly seen in immunocompetent patients.Eighty-two percent of patients (28 out of 34) received trimethoprim-sulfamethoxazole-containing regimens and median antibiotic treatment duration was 24 weeks (range, 12-120) for hematogenous infections and 12 weeks (range, 6-24) for direct inoculations. Outcome was favorable in 27 cases despite unsystematic surgical management (17 cases) without sequelae in 70% of the cases.Nocardia arthritis is rare but its management is complex and should rely on a combined approach with rheumatologist, infectious diseases expert, and surgeon.

Although the range of biocatalysts available for the synthesis of enantiomerically pure chiral amines continues to expand, few existing methods provide access to secondary amines. To address this shortcoming, we have over-expressed the gene for an ( R )-imine reductase [( R )-IRED] from Streptomyces sp. GF3587 in Escherichia coli to create a recombinant whole-cell biocatalyst for the asymmetric reduction of prochiral imines. The ( R )-IRED was screened against a panel of cyclic imines and two iminium ions and was shown to possess high catalytic activity and enantioselectivity. Preparative-scale synthesis of the alkaloid ( R )-coniine (90 % yield; 99 % ee ) from the imine precursor was performed on a gram-scale. A homology model of the enzyme active site, based on the structure of a closely related ( R )-IRED from Streptomyces kanamyceticus , was constructed and used to identify potential amino acids as targets for mutagenesis.

The ability of urea-linked oligomers of achiral diamines (achiral analogues of the well-established chiral oligourea foldamers) to adopt helical conformations was explored spectroscopically. Up to four achiral units were ligated either to a well-formed helical trimer or to a single chiral diamine, and the extent to which they adopted a screw-sense preference was determined by NMR and CD. In the best performing cases, a trimeric chiral oligourea and even a single cis-cyclohexanediamine monomer induced folding into a helical conformation.

Among numerical formats available to express probability, ratios are extensively used in risk communication, perhaps because of the health professional's intuitive sense of their clarity and simplicity. Moreover, health professionals, in the attempt to make the data more meaningful, tend to prefer proportions with a numerator of 1 and shifting denominators (e.g., 1 in 200) rather than equivalent rates of disease per unit of population exposed to the threat (e.g., 5 in 1000). However, in a series of 7 experiments, it is shown that individual subjective assessments of the same probability presented through proportions rather than rates vary significantly. A 1-in-X format (e.g., 1 in 200) is subjectively perceived as bigger and more alarming than an N-in-X*N format (e.g., 5 in 1000). The 1-in-X effect generalizes to different populations, probabilities, and medical conditions. Further-more, the effect is not attenuated by a communicative intervention (verbal analogy), but it disappears with an icon array visual aid.