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This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO 2 ). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle─82%, compared to 59% from preceding decades─as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.

Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds with human absorption data and ∼10,000 AbbVie tool compounds (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical trends. We introduced a high-throughput "polarity reduction" descriptor: ETR, the EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 and PROTAC subsets for specialized drug design strategies for effective absorption. Our methods and guidelines refine drug design by providing innovative in vitro approaches, enhancing physicochemical property optimization, and enabling accurate predictions of intestinal absorption in the complex bRo5 domain.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery. By examining chemical shift perturbations in 2D [ 1 H, 13 C-HSQC] spectra of isotopically labeled IL17A, we discovered fragments binding the cytokine at a previously undescribed site near the IL17A C-terminal region, albeit with weak affinity (> 250 µM). Importantly this binding location was distinct from previously known chemical matter modulating cytokine responses. Subsequently through analog screening, we identified related compounds that bound symmetrically in this novel site with two copies. From this observation we employed a linking strategy via structure-based drug design and obtained compounds with increased binding affinity (< 50 nM) and showed functional inhibition of IL17A-induced cellular signaling (IC 50 ~1 µM). We also describe a fluorescence-based probe molecule suitable to discern/screen for additional molecules binding in this C-terminal site., (© 2022. The Author(s).)

In the past decade or so there has been a dramatic increase in the number of computational applications and tools that have been developed to enable medicinal chemists to prosecute modern drug discovery programs more efficiently. The upsurge of user-friendly, well-designed computational tools that enable structure-based drug design (SBDD) and cheminformatics (CI)-based drug design has equipped the medicinal chemist with an arsenal of tools and applications that significantly augments the entire design process, thereby enhancing the speed and efficiency of the design-make-test-analyze cycle. Modern computational applications and tools transcend all areas of drug discovery, and most savvy medicinal chemists can employ them effectively in a myriad of drug discovery applications. Indeed, the sheer scope and breadth of tools available to the medicinal chemist is vast and, to our knowledge, has not been comprehensively reviewed. In this article we have catalogued many computational tools, platforms, and applications that are currently available, with four main areas highlighted: commercially available tools/platforms, open-source applications, internally developed platforms (software tools developed within a pharma or biotech organization), and artificial intelligence/machine learning-based platforms. For ease of interpretation, for these categories we provide tables organized by vendor or organization name, the name of the application, whether the tool/application is employed predominantly for SBDD or CI-based design, and a summary of the main function of the tools, with associated hyperlinks to vendor Web sites. We have tried to be as comprehensive and as inclusive as possible; however, the pace of development of new and existing tools is so rapid that there may be omissions with respect to newly developed tools and current versions of the software., Competing Interests: The authors declare the following competing financial interest(s): Both P.C. and R.G. are/were employees of AbbVie at the time of this study. The design, study content, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication., (© 2022 American Chemical Society.)

Phenols and phenolic ethers are significant scaffolds recurring both in nature and among approved small-molecule pharmaceuticals. This compendium presents the first comprehensive compilation and analysis of the structures of U.S. FDA-approved molecules containing phenol or phenolic ether fragments. This dataset comprises 371 structures, which are strongly represented by natural products. A total of 55 of the compounds described here are on the World Health Organization's list of essential medicines. Structural analysis reveals significant differences in the physicochemical properties imparted by phenols versus phenol ethers, each having benefits and drawbacks for drug developability. Despite trends over the past decade to increase the fraction of sp 3 centers in drug leads, thereby "escaping flatland", phenols and phenolic ethers are represented in 62% of small-molecule drugs approved in 2020, suggesting that this aromatic moiety holds a special place in drugs and natural products.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

The FDA Green Book is a list of all drug products that have been approved by the FDA for use in veterinary medicine. The Green Book, as published, lacks structural information corresponding to approved drugs. To address this gap, we have compiled the structural data for all FDA Green Book drugs approved through the end of 2019. Herein we discuss the relevance of this data set to human drugs in the context of structural classes and physicochemical properties. Analysis reveals that physicochemical properties are highly optimized and consistent with a high probability of favorable drug metabolism and pharmacokinetic properties, including good oral bioavailability for most compounds. We provide a detailed analysis of this data set organized on the basis of structure and function. Slightly over half (51%) of vet drugs are also approved in human medicine. Combination drugs are biologics are also discussed.

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp 3 rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection., Competing Interests: The authors declare the following competing financial interest(s): PBC is an employee of Abbvie. BC and KIBM are employees of their respective universities, co-founders and owners of Photodiversity Ltd. The design, study content, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication., (Copyright © 2020 American Chemical Society.)

Background: Acute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation., Method: COX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection., Results: Pigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = -0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = -0.760 and R = -0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3., Conclusion: Downregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The four B-family DNA polymerases α, δ, ϵ and ζ cooperate to accurately replicate the eukaryotic nuclear genome. Here, we report that a Saccharomyces cerevisiae strain encoding the pol2-16 mutation that lacks Pol ϵ's polymerase and exonuclease activities has increased dNTP concentrations and an increased mutation rate at the CAN1 locus compared to wild type yeast. About half of this mutagenesis disappears upon deleting the REV3 gene encoding the catalytic subunit of Pol ζ. The remaining, still strong, mutator phenotype is synergistically elevated in an msh6Δ strain and has a mutation spectrum characteristic of mistakes made by Pol δ. The results support a model wherein slow-moving replication forks caused by the lack of Pol ϵ's catalytic domains result in greater involvement of mutagenic DNA synthesis by Pol ζ as well as diminished proofreading by Pol δ during replication., (Published by Oxford University Press on behalf of Nucleic Acids Research 2019.)

Fragment-based drug discovery (FBDD) is a well-established technology for lead compound generation in drug discovery. As this technology has evolved, the design of fragments for screening has also evolved to engender not just an understanding of the role of modulating the physicochemical properties of fragments (Rule of Three, Ro3) but also the importance and implications of incorporating shape and, in particular, 3D characteristics into fragments. Herein, we describe the design and synthesis of pyrrolidine-based fragments with good fragment-like (Ro3) physicochemical properties that effectively sample three-dimensional molecular space., Competing Interests: The authors declare the following competing financial interest(s): P.C. and P.E. are employees of AbbVie, and U.R. was an employee during the time of this study. The design, study content, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Note that P.G. has received research funding and speaker fees from AbbVie. N.H. is an employee of Washington State University and has nothing to disclose.

In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp 3 )-H arylation of alicyclic amines for applications in fragment-based drug discovery (FBDD). We apply this method to the synthesis of a series of 6-arylated 3-azabicyclo[3.1.0]hexanes that are rule-of-three compliant fragments. Several modifications were made to the Pd-catalyzed C-H arylation method to enhance its utility in fragment synthesis. These include the use of microwave heating to shorten reaction times to under 1 h and the development of new approaches for directing group cleavage. Finally, we demonstrate that this fragment library falls within desirable physicochemical space for FBDD applications.

Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.

To investigate nuclear DNA replication enzymology in vivo, we have studied Saccharomyces cerevisiae strains containing a pol2-16 mutation that inactivates the catalytic activities of DNA polymerase ε (Pol ε). Although pol2-16 mutants survive, they present very tiny spore colonies, increased doubling time, larger than normal cells, aberrant nuclei, and rapid acquisition of suppressor mutations. These phenotypes reveal a severe growth defect that is distinct from that of strains that lack only Pol ε proofreading (pol2-4), consistent with the idea that Pol ε is the major leading-strand polymerase used for unstressed DNA replication. Ribonucleotides are incorporated into the pol2-16 genome in patterns consistent with leading-strand replication by Pol δ when Pol ε is absent. More importantly, ribonucleotide distributions at replication origins suggest that in strains encoding all three replicases, Pol δ contributes to initiation of leading-strand replication. We describe two possible models.

Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer., Competing Interests: The authors have declared that no competing interest exists.

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

The selection of the highest quality chemical matter from high throughput screening (HTS) is the ultimate aim of any triage process. Typically there are many hundreds or thousands of hits capable of modulating a given biological target in HTS with a wide range of physicochemical properties that should be taken into consideration during triage. Given the multitude of physicochemical properties that define drug-like space, a system needs to be in place that allows for a rapid selection of chemical matter based on a prioritized range of these properties. With this goal in mind, we have developed a tool, coined Abbott Physicochemical Tiering (APT) that enables hit prioritization based on ranges of these important physicochemical properties. This tool is now used routinely at Abbott to help prioritize hits out of HTS during the triage process. Herein we describe how this tool was developed and validated using Abbott internal high throughput ADME data (HT-ADME)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To describe a consensus review of optimal perioperative care in colorectal surgery and to provide consensus recommendations for each item of an evidence-based protocol for optimal perioperative care., Data Sources: For every item of the perioperative treatment pathway, available English-language literature has been examined., Study Selection: Particular attention was paid to meta-analyses, randomized controlled trials, and systematic reviews., Data Extraction: A consensus recommendation for each protocol item was reached after critical appraisal of the literature by the group., Data Synthesis: For most protocol items, recommendations are based on good-quality trials or meta-analyses of such trials., Conclusions: The Enhanced Recovery After Surgery (ERAS) Group presents a comprehensive evidence-based consensus review of perioperative care for colorectal surgery. It is based on the evidence available for each element of the multimodal perioperative care pathway.

As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.

A multidisciplinary approach for patients who will undergo colonic resection was introduced in 2006 and 2007 in 26 Dutch hospitals, following several other European centres. This approach aims to place the patient in an optimal metabolic state before operation, with subsequent rapid mobilisation and resumption of oral intake of liquids and solid food. The surgeon, anaesthetist, and nursing staff collaborate in this approach, each taking responsibility for specific tasks. The anaesthesiological tasks consist of withholding preoperative intake of drink and food, appropriate pain reduction, perioperative fluid balance management, use of inotropic and vasopressor drugs, prevention of post-operative nausea and vomiting, and addressing possible immunological consequences of surgery.

Purpose of Review: An estimated 0.5-4% of pregnant patients have cardiac disease, such as rheumatic disease, which is decreasing in Western countries, uncorrected congenital heart disease, cardiomyopathy and ischaemic heart disease. There has been an increase in maternal mortality due to cardiac causes. Congenital heart disease is becoming the most common source of cardiac problems in the pregnant patient, because patients are increasingly likely to survive to childbearing age with the improvement of surgery., Recent Findings: The increasing age of patients conceiving their first child is also an important factor. A comprehensive understanding of the physiology of pregnancy and the pathophysiology of maternal cardiac disease is of great importance for anaesthesiologists, gynaecologists and cardiologists involved in peripartum care., Summary: We try to give a brief and comprehensive review on this topic.

Purpose of Review: Refined techniques and skills have enabled sophisticated prenatal diagnosis in utero and resulted in the newly evolving specialty of fetal surgery in a few centres worldwide. Most of the procedures performed today have been preceded by extensive experimental research in animals, whereas fetal anaesthesia is mainly based on clinical experience and a few studies performed in pregnant sheep., Recent Findings: Major limitations of fetal surgery include the high frequency of preterm labour and delivery which may offset any fetal benefit of the surgical procedure. The development of more potent tocolytic drugs than the drugs currently available may thus be compared to the meaning of potent immunosuppressive agents in organ transplantation. Fetal mortality and maternal morbidity consequently lead to a more cautious way of treatment, as with the development of endoscopic fetal surgery., Summary: The invasive fetal surgery is still considered as being in a research stage in most cases. Therefore most procedures are performed as minimally invasive, avoiding substantial risks by accessing the uterus through minimal openings. Some new devices are under investigation for monitoring the myometrial electrical activity and mechanical contractility and the fetal electroencephalogram, the continuous monitoring of the fetal arterial oxygen saturation, PO2 and PCO2, and for monitoring fetal cerebral oxygenation, blood volume and blood flow by near infrared spectroscopy.

The development of an effective chiral auxiliary for hydroxyalkyl radicals is delineated. Both the 2-tetrahydropyranyl (THP) and tri-O-benzyl-2-deoxy-alpha-D-glucopyranosyl (GLU) auxiliaries resulted in diastereoselective radical additions to methyl acrylate at -78 degrees C (ds = 6/1 and 11/1, respectively). The developing stereochemistry at the radical center was completely under auxiliary control. Correlation experiments showed that the D-GLU auxiliary led to attack on the radical Si-face. The selectivity of these radical additions dropped-off considerably when the more reactive 2-nitropropene trap was employed. Computational studies suggested that the observed facial selectivity was due primarily to entropic factors in the transition state but that a smaller temperature-dependent enthalpic contribution was also involved. It was hypothesized that incorporation of a quaternary center at C-6 (THP numbering) would restore the facial selectivity with more reactive radical traps by restricting the orientations available to the incoming alkene. In the event, the trans-6-tert-butyltetrahydropyranyl (tBu-THP) auxiliary resulted in very good diastereoselection with 2-nitropropene (ds = 35/1 at -78 degrees C, 15/1 at 0 degrees C, and 8/1 at RT) as did the tri-O-benzyl-6,6-dimethyl-2-alpha-D-deoxyglucopyranosyl (diMe-GLU) auxiliary during additions to ethyl alpha-trifluoroacetoxyacrylate (ds = 10/1 at 0 degrees C). A protocol for recovery of the sugar-derived chiral auxiliaries was also established. This work sets the stage for the development of a novel approach to 1, 3, 5.(2n + 1) polyols based on iterative radical homologation as well as the application of these pyranosidic auxiliaries to other synthetically important reactions.

We present a brief overview of recent literature concerning some of the drugs used in pregnancy, labour and delivery. Obstetric anaesthesia continues to evolve through the reuse of old drugs such as magnesium sulphate or the manipulation of current drugs (e.g. propofol for emesis) in order to improve patient outcome. Pregnant women have traditionally been therapeutic orphans. The use of new agents such as levobupivacaine and ropivacaine in obstetric patients lags behind that of their non-pregnant counterparts. However, this gap is decreasing and these new drugs offer benefits to the parturient woman.

A novel approach to controlling the diastereofacial selectivity of intramolecular dipolar cycloadditions of azomethine ylides (cf. 9 --> 8) by varying the structure a silicon-based tether is described. A correlation is found between the length of the tether dipolarophile conjugate (TDC) and the observed sense of diastereocontrol. Azomethine ylides incorporating longer [OSiPh(2)OCH(2)CH(2)OCOCH=CH(2)], [OSi(i-Pr)(2)OSi(i-Pr)(2)OCH(2)CH=CH(2)], and [OSiPh(2)OCH(2)CH=CH(2)] TDCs favor endo-si attack (14 --> 16, 19 --> 20, and 21 --> 22) while the shorter TDC [OSiR(2)CH(2)CH=CH(2)] leads to a reversal in selectivity favoring the endo-re product (23a,b --> 24a,b). Structures of the cycloadducts have been assigned on the basis of selected X-ray diffraction data in combination with chemical/spectral correlation experiments. The work described herein represents a conceptually new approach to stereocontrol and extends the use of silicon-based tethers in asymmetric synthesis.