Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Risk Factors for Severe Maternal Morbidity Among Women Enrolled in Mississippi Medicaid.

Importance: Mississippi has one of the highest rates of severe maternal morbidity (SMM) in the US, and SMMs have been reported to be more frequent among Medicaid-insured women. A substantial proportion of pregnant women in Mississippi are covered by Medicaid; hence, there is a need to identify potential risk factors for SMM in this population. Objective: To examine the associations of health care access and clinical and sociodemographic characteristics with SMM events among Mississippi Medicaid-enrolled women who had a live birth. Design, Setting, and Participants: A nested case-control study was conducted using 2018 to 2021 Mississippi Medicaid administrative claims database. The study included Medicaid beneficiaries aged 12 to 55 years who had a live birth and were continuously enrolled throughout their pregnancy period and 12 months after delivery. Individuals in the case group had SMM events and were matched to controls on their delivery date using incidence density sampling. Data analysis was performed from June to September 2022. Exposure: Risk factors examined in the study included sociodemographic factors (age and race), health care access (distance from delivery center, social vulnerability index, and level of maternity care), and clinical factors (maternal comorbidity index, first-trimester pregnancy-related visits, and postpartum care). Main Outcomes and Measures: The main outcome of the study was an SMM event. Adjusted odds ratio (aORs) and 95% CIs were calculated using conditional logistic regression. Results: Among 13 485 Mississippi Medicaid-enrolled women (mean [SD] age, 25.0 [5.6] years; 8601 [63.8%] Black; 4419 [32.8%] White; 465 [3.4%] other race [American Indian, Asian, Hispanic, multiracial, and unknown]) who had a live birth, 410 (3.0%) were in the case group (mean [SD] age, 26.8 [6.4] years; 289 [70.5%] Black; 112 [27.3%] White; 9 [2.2%] other race) and 820 were in the matched control group (mean [SD] age, 24.9 [5.7] years; 518 [63.2%] Black; 282 [34.4%] White; 20 [2.4%] other race). Black individuals (aOR, 1.44; 95% CI, 1.08-1.93) and those with higher maternal comorbidity index (aOR, 1.27; 95% CI, 1.16-1.40) had higher odds of experiencing SMM compared with White individuals and those with lower maternal comorbidity index, respectively. Likewise, an increase of 100 miles (160 km) in distance between beneficiaries' residence to the delivery center was associated with higher odds of experiencing SMM (aOR, 1.14; 95% CI, 1.07-1.20). Conclusions and Relevance: The study findings hold substantial implications for identifying high-risk individuals within Medicaid programs and call for the development of targeted multicomponent, multilevel interventions for improving maternal health outcomes in this highly vulnerable population.

Through a computer monitor darkly: artificial intelligence in absorption, distribution, metabolism and excretion science.

Artificial Intelligence (AI) is poised or has already begun to influence highly absorption, distribution, metabolism and excretion (ADME) science. It is not in the area expected, that of superior modelling of ADME data to increase its predictive power. It is influencing traditional exhaustive and careful literature research by providing almost perfect summaries of existing information. This will highly influence how people study, graduate and progress in the ADME sciences. The literature contains many flaws, protein binding influence on unbound drug concentration, is one of the examples cited, and without direction AI may help to popularise them.ADME science has a relatively small number of key assays and values but these are produced under widely varying conditions so large data sets, the best substrate for artificial intelligence, are not readily available to produce new more predictive systems. The use of AI to enrich the data bases may be a near term goal.AI is already contributing in other areas such as technical skill assimilation, maintenance of complex instruments (combined with virtual reality) and the processing of pharmacovigilance.

Association of antecedent statin use on 30-day, 60-day and 90-day mortality among Mississippi Medicaid beneficiaries diagnosed with COVID-19.

OBJECTIVE: To assess if the antecedent statin use was associated with all-cause death among COVID-19 patients enrolled in Medicaid. DESIGN: Cohort study. SETTING: Mississippi Medicaid population. PARTICIPANTS: This study included 10 792 Mississippi Medicaid-enrolled patients between 18 and 64 years of age with a confirmed COVID-19 diagnosis from March 2020 to June 2021. INTERVENTION: Antecedent statin use, which was determined by a record of statin prescription in the 90-day period prior to the COVID diagnosis. MAIN OUTCOME MEASURES: The outcomes of interest included mortality from all cause within 30 days, 60 days and 90 days after index. RESULTS: A total of 10 792 patients with COVID-19 met the inclusion and exclusion criteria, with 13.1% of them being antecedent statin users. Statin users were matched 1:1 with non-users based on age, sex, race, comorbidities and medication use by propensity score matching. In total, the matched cohort consisted of 1107 beneficiaries in each group. Multivariable logistic regression showed that statin users were less likely to die within 30 days (adjusted OR: 0.51, 95% CI: 0.32 to 0.83), 60 days (OR: 0.56, 95% CI: 0.37 to 0.85) and 90 days (OR: 0.55, 95% CI: 0.37 to 0.82) after diagnosis of COVID-19. Those with low-intensity/moderate-intensity statin use had significantly lower mortality risk in the 60-day and the 90-day follow-up period, while the high intensity of statin use was only found to be significantly associated with a lower odd of mortality within 30 days post index. CONCLUSION: After COVID infection, Medicaid beneficiaries who had taken statins antecedently could be at lower risk for death. For patients with chronic conditions, continuity of care is crucial when interruptions occur in their medical care. Further research is required to further investigate the potential mechanisms and optimal use of statins in COVID-19 treatment.

Endoscopic blind limb reduction with septotomy: a novel endoscopic approach to candy cane syndrome after Roux-en-Y gastric bypass.

Video 1The endoscopic blind limb reduction with septotomy procedure.

Anti-infectives Developed as Racemic Drugs in the 21st Century: Norm or Exception?

This viewpoint outlines the case for developing new chemical entities (NCEs) as racemates in infectious diseases and where both enantiomers and racemate retain similar on- and off-target activities as well as similar PK profiles. There are not major regulatory impediments for the development of a racemic drug, and minimizing the manufacturing costs becomes a particularly important objective when bringing an anti-infective therapeutic to the marketplace in the endemic settings of infectious diseases.

Teaching Old Polymers New Tricks: Improved Synthesis and Anomalous Crystallinity for a Lost Semi-Fluorinated Polyaryl Ether via Interfacial Polymerization of Hexafluoroacetone Hydrate and Diphenyl Ether.

A practical and direct electrophilic polymerization of hexafluoroacetone hydrate with diphenyl ether toward the preparation of semi-fluorinated polyaryl ethers (PAE) is reported. Electrophilic aromatic substitution (EAS) polymerization under interfacial conditions with phase transfer catalyst (Aliquat 336) proceeds in trifluoromethanesulfonic anhydride by generation of trifluoromethanesulfonic acid and the protonated hexafluoroacetone (HFA) in situ affording 1,1,1,3,3,3-hexafluoroisopropylidene (6F) PAE with high regioselectivity (4,4'-DPE) and high molecular weight (≈60 kDa). Although first reported in a 1966 US Patent by DuPont using harsh conditions, improved synthetic methods or modern characterization has not been disclosed until now. Despite the presence of the 6F group, known to impart disordered morphology, this simple semi-fluorinated PAE exhibits anomalous crystallinity with polymorphic melting points (Tm ) ranging from 230-309 °C, high solubility in common organic solvents, a glass transition (Tg ) of 163 °C, and thermo-oxidative stability above 500 °C. Tough optically clear films prepared from solution give transmittance higher than 90% throughout the visible region. Synthesis, mechanistic aspects, and characterization including surface and dielectric properties are discussed.

Endoscopic rescue of anastomotic dehiscence after urgent gastric bypass revision.

Video 1.

Ring-Forming Polymerization toward Perfluorocyclobutyl and Ortho-Diynylarene-Derived Materials: From Synthesis to Practical Applications.

Many desirable characteristics of polymers arise from the method of polymerization and structural features of their repeat units, which typically are responsible for the polymer's performance at the cost of processability. While linear alternatives are popular, polymers composed of cyclic repeat units across their backbones have generally been shown to exhibit higher optical transparency, lower water absorption, and higher glass transition temperatures. These specifically include polymers built with either substituted alicyclic structures or aromatic rings, or both. In this review article, we highlight two useful ring-forming polymer groups, perfluorocyclobutyl (PFCB) aryl ether polymers and ortho-diynylarene- (ODA) based thermosets, both demonstrating outstanding thermal stability, chemical resistance, mechanical integrity, and improved processability. Different synthetic routes (with emphasis on ring-forming polymerization) and properties for these polymers are discussed, followed by their relevant applications in a wide range of aspects.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts.

A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

Correction: Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

Correction for 'Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines' by Patrick Kielty et al., Chem. Commun., 2019, 55, 14665-14668, DOI: 10.1039/C9CC08261A.

The Critical Role of Passive Permeability in Designing Successful Drugs.

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.

Single Anastomosis Duodenal Switch: 1-Year Outcomes.

INTRODUCTION: Single-anastomosis duodenal switch has been suggested to be an effective bariatric procedure that offers excellent weight loss and by lengthening the common channel the potential to reduce micronutrient deficiencies. PURPOSE: To evaluate the weight loss, comorbidity resolution and the 1-year nutritional outcomes of the single-anastomosis duodenal switch (SADS) procedure. SETTING: Multiple US Hospitals. METHODS: From October 2014 to January 2017, 120 patients were enrolled at six sites across the USA and underwent the SADS procedure. Weight loss, comorbidities, quality of life, and adverse events were followed post-procedure for 12 months. RESULTS: At 1, 6, and 12 months, 98.3%, 85.5%, and 77.1% of the patients were available for assessment, respectively. At 12 months, patients showed significantly reduced body mass index when compared to baseline (46.8 ± 5.8 vs 29.8 ± 4.4, P < 0.001 respectively). Sixty-five patients had type 2 diabetes at baseline; however, 11 patients lost to follow-up. Of the available data (54 patients), 96.3% of the patients had a resolution of type 2 diabetes by 12 months with a mean A1C reduction from 7.8 ± 1.6 to 5.3 ± 0.7. Additionally, there were reductions in hyperlipidemia, sleep apnea, and hypertension at 12 months. Patient gastroesophageal reflux disease satisfaction and quality of life (SF-36) scores were significantly higher at 12 months post-procedure (P < 0.001 in all cases) while 12-month protein levels remained at normal values. There were abnormalities of parathyroid hormone and vitamin D at 1 year with all other nutritional markers being not significantly different at 1 year from baseline. There were 10, IIIb, or greater complications according to the Clavien-Dindo scoring system during the study period, not all of which were related to the surgery. CONCLUSIONS: SADS is a highly efficacious weight loss procedure with significant comorbidity reduction at 1 year. At 1 year, complications and vitamin and mineral deficits appear to be consistent with other malabsorption operations. Long-term follow-up is needed, especially around complications and vitamin deficiencies.

Dose Predictions for Drug Design.

The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a reasonable dose and dose regimen in an animal model. Through the early 2000s, dose predictions were generated at candidate nomination and then refined during clinical development. Currently, dose predictions can be made early in drug discovery to enable drug design. Dose predictions at this stage can identify critical drug properties for a viable dose regimen and provide clinically relevant context to lead optimization. In this paper, we give an overview of the opportunities and challenges associated with dose prediction for drug design. A number of general considerations, approaches, and case examples are discussed.

An in vitro toolbox to accelerate anti-malarial drug discovery and development.

BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines.

In nature, the unmasking of heterocyclic quinones to form stabilized quinone methide radicals is achieved using reductases (bioreduction). Herein, an alternative controllable room-temperature, visible-light activated protocol using alkoxyamines and bis-alkoxyamines is provided. Selective synthetic modification of the bis-alkoxyamine, allowed chromophore deactivation to give one labile alkoxyamine moiety.

The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro.

Intracellular and Intraorgan Concentrations of Small Molecule Drugs: Theory, Uncertainties in Infectious Diseases and Oncology, and Promise.

The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment. For most highly lipid permeable drugs, this uniform unbound concentration is expected to apply. However, many compounds have restricted lipoidal permeability and are subjected to transport/clearance processes causing a gradient between intracellular and extracellular unbound concentrations even at steady state. Additional concerns arise where the drug target resides in a site of limited vascularity. Many misleading assumptions about drug concentrations and access to drug targets are based on total drug. Correction, if made, is usually by measuring tissue binding, but this is limited by the lack of homogenicity of the organ or compartment. Rather than looking for technology to measure the unbound concentration it may be better to focus on designing high lipoidal permeable molecules with a high chance of achieving a uniform unbound drug concentration. It is hoped this paper will stimulate greater understanding of the path from circulation to cell interior, and thereby in part avoid or minimize the need to provide the experimentally very determining, and sometimes still questionable, answer to this problem.