Bristol-Myers Squibb (Netherlands)

The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.

This updated Good Publication Practice (GPP) guideline, known as GPP3, builds on earlier versions and provides recommendations for individuals and organizations that contribute to the publication of research results sponsored or supported by pharmaceutical, medical device, diagnostics, and biotechnology companies. The recommendations are designed to help individuals and organizations maintain ethical and transparent publication practices and comply with legal and regulatory requirements. These recommendations cover publications in peer-reviewed journals and presentations (oral or poster) at scientific congresses. The International Society for Medical Publication Professionals invited more than 3000 professionals worldwide to apply for a position on the steering committee, or as a reviewer, for this guideline. The GPP2 authors reviewed all applications (n = 241) and assembled an 18-member steering committee that represented 7 countries and a diversity of publication professions and institutions. From the 174 selected reviewers, 94 sent comments on the second draft, which steering committee members incorporated after discussion and consensus. The resulting guideline includes new sections (Principles of Good Publication Practice for Company-Sponsored Medical Research, Data Sharing, Studies That Should Be Published, and Plagiarism), expands guidance on the International Committee of Medical Journal Editors' authorship criteria and common authorship issues, improves clarity on appropriate author payment and reimbursement, and expands information on the role of medical writers. By following good publication practices (including GPP3), individuals and organizations will show integrity; accountability; and responsibility for accurate, complete, and transparent reporting in their publications and presentations.

Abstract Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. N ‐hydroxyphthalimide (NHPI) based redox‐active esters were found to be convenient starting materials for simple, thermal, Ni‐catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH 3 ) or an electron‐deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.

We report that Ni(COD)(DQ) (COD=1,5-cyclooctadiene, DQ=duroquinone), an air-stable 18-electron complex originally described by Schrauzer in 1962, is a competent precatalyst for a variety of nickel-catalyzed synthetic methods from the literature. Due to its apparent stability, use of Ni(COD)(DQ) as a precatalyst allows reactions to be conveniently performed without use of an inert-atmosphere glovebox, as demonstrated across several case studies.

Abstract Herein we report acid‐directed β‐C(sp 3 )‐H arylation of α‐amino acids enabled by pyridine‐type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc‐protected unnatural amino acids in three steps. The pyridine‐type ligands are crucial for the development of this new C(sp 3 )‐H arylation.

Abstract We report the development of palladium(0)‐catalyzed syn ‐selective 1,2‐carboboration and ‐silylation reactions of alkenes containing cleavable directing groups. With B 2 pin 2 or PhMe 2 Si‐Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono‐, di‐, tri‐ and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2‐carboboration of electron‐rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck‐type alkene 1,2‐difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio‐ and stereocontrol.

Two roads diverged: The mechanism of in situ PdII catalyst activation to generate an active {LnPd0} catalyst from an air-stable PdII precursor was examined using the standard conditions of a Miyaura borylation reaction. Two pathways for catalyst activation exist under these conditions, producing two structurally and chemically distinct {LnPd0} complexes (see scheme). As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

This report describes a three-component, Ni-catalyzed reductive coupling that enables the convergent synthesis of tertiary benzhydryl amines, which are challenging to access by traditional reductive amination methodologies. The reaction makes use of iminium ions generated in situ from the condensation of secondary N-trimethylsilyl amines with benzaldehydes, and these species undergo reaction with several distinct classes of organic electrophiles. The synthetic value of this process is demonstrated by a single-step synthesis of antimigraine drug flunarizine (Sibelium) and high yielding derivatization of paroxetine (Paxil) and metoprolol (Lopressor). Mechanistic investigations support a sequential oxidative addition mechanism rather than a pathway proceeding via α-amino radical formation. Accordingly, application of catalytic conditions to an intramolecular reductive coupling is demonstrated for the synthesis of endo- and exocyclic benzhydryl amines.

A nickel-catalyzed conjunctive cross-coupling of alkenyl carboxylic acids, aryl iodides, and aryl/alkenyl boronic esters is reported. The reaction delivers the desired 1,2-diarylated and 1,2-arylalkenylated products with excellent regiocontrol. To demonstrate the synthetic utility of the method, a representative product is prepared on gram scale and then diversified to eight 1,2,3-trifunctionalized building blocks using two-electron and one-electron logic. Using this method, three routes toward bioactive molecules are improved in terms of yield and/or step count. This method represents the first example of catalytic 1,2-diarylation of an alkene directed by a native carboxylate group.

Epidemiologic studies in humans have demonstrated that infection with helminth parasites is associated with a reduced risk of developing autoimmune diseases. Mechanistic studies in mice have linked the protective effect of helminths on autoimmunity to the suppressive activity of helminth-induced regulatory T cells (Tregs) or Th2 cells. In this study, we demonstrate that treatment of mice with Fasciola hepatica excretory-secretory products (FHES) attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Protection was associated with a significant reduction in the infiltration of pathogenic Th1 and Th17 cells into the brain. Although FHES enhanced anti-inflammatory cytokine and Th2 responses, protection against EAE was independent of IL-4, IL-10, and Tregs. However, administration of FHES induced production of the type 2 cytokines IL-33 and IL-5, which promoted accumulation of eosinophils. FHES-induced expansion of eosinophils and protection against EAE was lost in IL-33(-/-) mice and upon neutralization of IL-5. Furthermore, transfer of FHES-induced or IL-33-induced eosinophils conferred protection against EAE. In addition, treatment of mice with recombinant IL-33 attenuated autoimmunity, and this was dependent on IL-5. To our knowledge, this study is the first to report a role for helminth-induced IL-5 and IL-33 in protection against autoimmunity.

OBJECTIVE: To examine the evidence that dopamine (DA) dysfunction contributes to melancholic depression. METHOD: Database (EMBASE, PsychLit and MEDLINE) searches using relevant key words were conducted and citations were scrutinized. RESULTS: In this paper, we assume that the definition of melancholia is contingent upon the presence of psychomotor disturbance (PMD). In melancholic depression PMD comprises both a cognitive and motor component and DA is found to be important in both. DA neurotransmission modulates cognition in particular in attention, adaptation and motivational processes and has a pivotal role in motor function. CONCLUSION: DA is a credible aetiological candidate for the PMD in melancholic depression. However, melancholia needs first to be characterized both clinically and in terms of its pathophysiology. In this regard, illnesses such as bipolar depression and Parkinson's disease warrant consideration as they provide suitable models of both the cognitive and motor aspects of PMD, and hold the necessary markers to better define melancholia.

Mycobacterium tuberculosis is a concern in patients with human immunodeficiency virus (HIV) infection. Rifampin (RIF), an agent used against M. tuberculosis, is contraindicated with most HIV protease inhibitors. Atazanavir (ATV) has clinical efficacy comparable to a standard of care regimen in naive patients and, when dosed with low-dose ritonavir (RTV), also in treatment-experienced patients. We evaluated here the safety and pharmacokinetics of ATV, resulting from three regimens of ATV, RTV, and RIF in 71 healthy subjects. The pharmacokinetics for ATV and RTV were assessed after 6 and 10 days of dosing with ATV 400 mg (n = 53) and with ATV-RTV at 300 and 100 mg (ATV/RTV 300/100; n = 52), respectively. Steady-state pharmacokinetics for ATV, RTV, RIF, and desacetyl-rifampin (des-RIF) were measured after 10 days of dosing of ATV/RTV/RIF 300/100/600 (n = 17), ATV/RTV/RIF 300/200/600 (n = 17), or ATV/RTV/RIF 400/200/600 (n = 14). An RIF 600-alone arm was enrolled as a control group (n = 18). With ATV/RTV/RIF 400/200/600, ATV area under the concentration-time curve values were comparable, but the C(min) values were lower relative to ATV 400 alone. ATV exposures were substantially reduced for the other RIF-containing regimens relative to ATV 400 alone and for all regimens relative to ATV/RTV 300/100 alone. RIF and des-RIF exposures were 1.6- to 2.5-fold higher than with RIF 600 alone. The incidence of grade 3/4 alanine aminotransferase/aspartate aminotransferase values was limited to 1 subject each in both the ATV/RTV/RIF 300/200/600 and the ATV/RTV/RIF 400/200/600 treatments. Coadministration of ATV with RIF was safe and generally well tolerated. Since ATV exposures were reduced in all regimens, ATV and RIF should not be coadministered at the dosing regimens studied.

Abstract Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. N ‐hydroxyphthalimide (NHPI) based redox‐active esters were found to be convenient starting materials for simple, thermal, Ni‐catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH 3 ) or an electron‐deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry.

The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin ( 1 ), is described from the two unnatural amino acid derivatives 2 and 3 . After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4 . Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1 . While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9 . Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.

Metformin (MET), CAS 1115-70-4 (Metformin hydrochloride), is an antidiabetic drug with high usage in North America and Europe and has become the subject of regulatory interest. A pharmaceutical industry working group investigated environmental risks of MET. Environmental fate and chronic effects data were collated across the industry for the present risk assessment. Predicted environmental concentrations (PECs) for MET were modeled for the USA and Europe using the PhATE and GREAT-ER models, respectively. PECs were compared with measured environmental concentrations (MECs) for the USA and Europe. A predicted no effect concentration (PNEC) of 1 mg/L for MET was derived by deterministic procedures, applying an assessment factor of 10 to the lowest no observed effect concentration (i.e., 10 mg/L) from multiple chronic studies with algae, daphnids and fish. The PEC/PNEC and MEC/PNEC risk characterization ratios were <1, indicating no significant risk for MET with high Margins of Safety (MOS) of >868. MET is known to degrade during wastewater treatment to guanylurea (GUU, CAS 141-83-3), which we have shown to further degrade. There are no GUU toxicity data in the literature; hence, chronic studies for GUU were conducted to derive a PNEC of 0.16 mg/L. PECs were derived for GUU as for MET, plus MECs were retrieved from the literature. The PEC/PNEC and MEC/PNEC risk characterization ratios for GUU were also <1, with an MOS of >6.5. Based on standard risk assessment procedures for both MET and its transformation product GUU, there is no significant risk to aquatic life.

A new ecstasy-like substance, meta-chlorophenylpiperazine (mCPP), has been detected in street drugs in the Netherlands. Theoretically, mCPP possesses the potential to become a non-neurotoxic alternative for methylenedioxymethamphetamine (MDMA), the regular psychoactive substance of ecstasy. Since its introduction on the Dutch market of synthetic drugs, the percentage of mCPP-containing tablets has increased, including both tablets that contain only mCPP and tablets containing a combination of mCPP and MDMA. These tablets occur in many different colours, shapes and sizes and with various logos, making it impossible to distinguish mCPP-containing tablets from regular MDMA tablets. In addition, the reports of users concerning the effects of mCPP are predominantly negative. All these aspects together lead to the conclusion that mCPP is an undesired addition to the ecstasy market from the user's perspective.

Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients.

OBJECTIVE: Previous reports of the RAPID-axSpA trial (NCT01087762) described the efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with axial spondyloarthritis (SpA), including ankylosing spondylitis (AS) and nonradiographic axial SpA. We report efficacy and safety data up to week 96 of the study. METHODS: The RAPID-axSpA trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Outcome variables included Assessment of SpondyloArthritis international Society criteria for 20% and 40% improvement in disease activity (ASAS20/40), ASAS partial remission responses (analyzed by nonresponder imputation), AS Disease Activity Score (ASDAS), ASDAS inactive disease, ASDAS major improvement, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Bath AS Metrology Index (BASMI) linear score (analyzed by the last observation carried forward method). Safety data were collected for patients treated with ≥1 dose of CZP. RESULTS: Of the 325 patients who were randomized, 218 received CZP from week 0. Of these, 93% completed week 24, 88% completed week 48, and 80% completed week 96. Improvements in ASAS responses were maintained to week 96 (for ASAS20, 67.4%, 72.0%, and 62.8% at weeks 24, 48, and 96, respectively), as well as improvements in ASDAS, BASDAI (mean score 3.3, 3.1, and 3.0 at weeks 24, 48, and 96, respectively), BASFI, and BASMI linear score. Comparable improvements were observed with both dosing regimens (200 mg every 2 weeks or 400 mg every 4 weeks) and in patients with AS and those with nonradiographic axial SpA. In the safety set, adverse events occurred in 279 patients (88.6%) and serious adverse events in 41 (13.0%). No deaths or malignancies were reported. CONCLUSION: Clinical improvements to week 24 in both CZP dosing regimens were sustained to week 96. Similar sustained improvements were observed in AS and nonradiographic axial SpA subpopulations. The safety profile was consistent with previous reports from RAPID-axSpA, with no new safety signals observed with longer exposure.