Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature.

In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.

Correction to: National dose reference levels in computed tomography-guided interventional procedures-a proposal.

The original version of this article, published on 02 May 2020, unfortunately contained a mistake.

National dose reference levels in computed tomography-guided interventional procedures-a proposal.

OBJECTIVES: To establish national reference levels (RLs) in interventional procedures under CT guidance as required by the 2013/59/Euratom European Directive. METHODS: Seventeen categories of interventional procedures in thoracic, abdominopelvic, and osteoarticular specialties (percutaneous infiltration, vertebroplasty, biopsy, drainage, tumor destruction) were analyzed. Total dose length product (DLP), number of helical acquisitions (NH), and total DLP for helical, sequential, or fluoroscopic acquisitions were recorded for 10 to 20 patients per procedure at each center. RLs were calculated as the 3rd quartiles of the distributions and target values for optimization process (TVOs) as the median. RLs and TVOs were compared with previously published studies. RESULTS: Results on 5001 procedures from 49 centers confirmed the great variability in patient dose for the same category of procedures. RLs were proposed for the DLPs and NHs in the seventeen categories. RLs in terms of DLP and NH were 375 mGy.cm and 2 NH for spinal or peri-spinal infiltration, 1630 mGy.cm and 3 NH for vertebroplasty, 845 mGy.cm and 4 NH for biopsy, 1950 mGy.cm and 8 NH for destruction of tumors, and 1090 mGy.cm and 5 NH for drainage. DLP and NH increased with the complexity of procedures. CONCLUSIONS: This study was the first nationwide multicentric survey to propose RLs for interventional procedures under CT guidance. Heterogeneity of practice in centers were found with different levels of patient doses for the same procedure. The proposed RLs will allow imaging departments to benchmark their practice with others and optimize their protocols. KEY POINTS: • National reference levels are proposed for 17 categories of interventional procedures under CT guidance. • Reference levels are useful for benchmarking practices and optimizing protocols. • Reference levels are proposed for dose length product and the number of helical acquisitions.

Renal Metastases from a Nasal Cavity Mixed Squamous Cell and Adenoid Cystic Carcinoma: A Case Report.

BACKGROUND Adenoid cystic carcinoma (ACC) is a very rare tumor with a high risk of loco-regional recurrence and potential distant metastases. Until now, only a few cases of renal metastases from ACC have been reported in the literature. CASE REPORT A 64-year-old, Caucasian, non-smoker female, 8 months after being treated by radio-chemotherapy for a squamous cell nasal cavity tumor, presented two renal lesions associated with lung and vertebral metastases. Histology was consisted with a metastasis from an ACC. The histological revision of the primary nasal tumor confirmed a squamous cells carcinoma with an adenoid cystic component that metastasized to the kidney. Renal lesions appeared hypometabolic at the ¹8F-fluorodeoxyglucose (¹8F-FDG) PET scan mimicking a primary renal tumor. The patient underwent a systemic, palliative chemotherapy by a weekly carboplatin/paclitaxel/cetuximab regimen that was well tolerated and allowed a lasting tumor control. CONCLUSIONS The particularity of this case relies on the rarity of renal metastasis from ACC, its difficult diagnosis, and the complexity of its management, as no standard chemotherapy has been validated for metastatic ACC, yet. In our case, a weekly carboplatin/paclitaxel/cetuximab regimen was administered leading to a durable tumor stabilization with an excellent patient's quality of life.

A paraneoplastic limbic encephalitis from an anorectal small cell neuroendocrine carcinoma: a case report.

BACKGROUND: Paraneoplastic limbic encephalitis (PLE) is a rare autoimmune neurological syndrome observed in cancer patients. PLE is difficult to diagnose and presents a variable response to treatment, depending on the characteristics of the tumor and neuronal autoantibodies. CASE PRESENTATION: A 64-year-old, Caucasian, non-smoker man presented with a rapidly developing cognitive impairment, personality change, spatial disorientation, and short-term memory loss associated with anorexia and cervical and inguinal lymph nodes. The 18F-FDG PET scan documented intensely hypermetabolic lymph nodes, which histologically corresponded to a metastasis from a small cell neuroendocrine carcinoma. The brain MRI revealed a high T2-weighted FLAIR signal of the hippocamps, consisted with a PLE. The presence of anti-neuronal Hu antibodies confirmed the diagnosis. The patient underwent plasmapheresis, associated to a systemic chemotherapy resulting in a partial and temporary improvement of the neurological symptoms. Four cycles of intravenous immunoglobulins were also necessary. After six cures of chemotherapy, the lymph node metastases regressed. However, a new anorectal lesion was detected and was histologically confirmed as a primary small cell neuroendocrine carcinoma, which was treated with concomitant chemoradiotherapy. At the end of this treatment, the patient showed a rapid tumor progression leading to his death. CONCLUSIONS: This case highlights the rare entity, PLE, which is difficult to diagnose and manage. In addition, this is the first published case of PLE associated with an anorectal small cell neuroendocrine carcinoma, which appeared after completion of systemic chemotherapy.

Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors.

Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils.

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor α (VEGF-α) by a minor subset of activated EpCAM+CD59+Ly-6D+ cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guérin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.

Application of the Tissue Composition-Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology.

The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatology and toxicology studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clinical candidate selection. Essential input parameters in whole-body physiologically based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (Vss). Mechanistic in vitro- and in silico-based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition-based model (TCM). Robust TCMs were initially developed for some preclinical species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biological membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting Vss and the dermis-to-plasma partition coefficients (Kp-dermis) of 68 drugs. The prediction of Kp-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclinical species. In general, up to 86% and 100% of the predicted Vss values are respectively within 2-fold and 3-fold errors compared to the experimentally determined values, whereas these numbers are 78% and 94% for Kp-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiologically based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclinical and clinical transdermal studies.

Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.

A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.

Peritoneal Myeloid Sarcoma in a Patient Treated for a Testicular Seminoma.

BACKGROUND Myeloid sarcoma is a rare extramedullary soft tissue neoplasm composed of myeloblastic cells, usually associated to hematologic tumor disorders and a poor prognosis. Its diagnosis is very difficult as radiological images are not specific. Histology and immunohistochemistry are necessary for an accurate diagnosis. CASE REPORT We report the case of 46-year-old, Caucasian, non-smoker male, treated in 2014 by orchiectomy and systemic chemotherapy for a stage IIB testicular seminoma. Considering the rapid increase of lactate dehydrogenase (LDH) levels without any evident medical reason, a computed tomography/positron emission tomography (CT/PET) scan was performed and revealing a diffuse, nodular, peritoneal tumor infiltration associated with multiple mesenteric and mediastinal adenopathies. Laparoscopy confirmed a diffuse tumor infiltration of the peritoneum. Histology and immunohistochemistry were consisted with the diagnosis of a myeloid monoblastic sarcoma. Cytology of bone marrow documented an monocytic acute myeloid leukemia. The patient started a systemic induction chemotherapy with high dose cytarabine and idarubicin that was complicated by an infectious pneumonia and colitis, and a grade IV thrombocytopenia leading to a brain subdural hemorrhage and quickly to patient's death. CONCLUSIONS We describe a rare, peritoneal, myeloid sarcoma in a young patient who had been treated by systemic chemotherapy for testicular seminoma 4 years earlier. The patient was clinically asymptomatic and presented only elevated LDH levels without any evident clinical reason. Considering the persistence of this biochemical abnormality, more investigations were performed leading to a diagnosis of peritoneal myeloid sarcoma associated with monocytic acute myeloid leukemia, probably secondary to the past chemotherapy.

Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.

The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

Sulfoximines as potent RORγ inverse agonists.

Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis.

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.

Breast metastasis from squamous cell carcinoma of the oropharynx: a case report.

BACKGROUND: Breast metastases from extramammary tumors are extremely rare, the most common primary tumors being contralateral breast carcinoma, followed by lung, gynecological, gastrointestinal, melanoma, and hematological cancers. Only a few cases deriving from head and neck squamous cell carcinoma have been reported in the literature to date. CASE PRESENTATION: We report a case of a 47-year-old Caucasian woman who presented to our hospital with a solitary breast lesion in the right upper external quadrant associated with multiple bone and visceral metastases. Two years before, she had undergone radical resection of a squamous cell carcinoma of the oropharynx (stage pT2, pN1), which was followed by adjuvant radiotherapy. Breast ultrasound showed a hypoechogenic tumor lesion of 4 cm in the right upper external quadrant that was associated with multiple axillary and infra-/supraclavicular adenopathies. A positron emission tomographic scan documented multiple visceral and bone metastases with a single hypermetabolic lesion of the right breast. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma. The patient died of acute respiratory insufficiency 1 month after her breast metastasis diagnosis and before starting any systemic antitumoral treatment. CONCLUSIONS: Although breast metastases are extremely rare, they should be considered in any patient with a history of cancer and confirmed by histology and immunohistochemistry because they are very difficult to distinguish from other primary breast tumors based only on clinical and radiological features. There are no standardized treatment guidelines for breast metastasis management. Surgery and radiotherapy can play a role in symptom palliation, but they do not have any relevant impact on survival, the prognosis being poor, with an estimated overall survival less than 1 year from diagnosis.

Identification of novel TACE inhibitors compatible with topical application.

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.

Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report.

BACKGROUND Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. CASE REPORT We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis.  CONCLUSIONS There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases.

Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists.

Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.