Ni-Catalyzed Carbon-Carbon Bond-Forming Reductive Amination.

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.

Decarboxylative Peptide Macrocyclization through Photoredox Catalysis.

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic method enables the efficient synthesis of cyclic peptides containing γ-amino acids and is tolerant of functionalities present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox method. To demonstrate the preparative utility of this method in the context of bioactive molecules, we synthesized COR-005, a somatostatin analogue that is currently in clinical trials.

Ligand-enabled ß-C-H arylation of α-amino acids using a simple and practical auxiliary.

Pd-catalyzed ß-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct ß-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of ß-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells.

Vascular endothelial cells are exposed to mechanical forces due to their presence at the interface between the vessel wall and flowing blood. The patterns of these mechanical forces (laminar vs. turbulent) regulate endothelial cell function and play an important role in determining endothelial phenotype and ultimately cardiovascular health. One of the key transcriptional mediators of the positive effects of laminar flow patterns on endothelial cell phenotype is the zinc-finger transcription factor, krüppel-like factor 2 (KLF2). Given its importance in maintaining a healthy endothelium, we sought to identify endothelial regulators of the KLF2 transcriptional program as potential new therapeutic approaches to treating cardiovascular disease. Using an approach that utilized both bioinformatics and targeted gene knockdown, we identified endothelial GPCRs capable of modulating KLF2 expression. Genetic screening using siRNAs directed to these GPCRs identified 12 potential GPCR targets that could modulate the KLF2 program, including a subset capable of regulating flow-induced KLF2 expression in primary endothelial cells. Among these targets, we describe the ability of several GPCRs (GPR116, SSTR3, GPR101, LGR4) to affect KLF2 transcriptional activation. We also identify these targets as potential validated targets for the development of novel treatments targeting the endothelium. Finally, we highlight the initiation of drug discovery efforts for LGR4 and report the identification of the first known synthetic ligands to this receptor as a proof-of-concept for pathway-directed phenotypic screening to identify novel drug targets.

A new methodology for quantitative LSPR biosensing and imaging.

A new quantitative analysis methodology for localized surface plasmon resonance (LSPR) biosensing which determines surface-receptor fractional occupancy, as well as an LSPR imaging technique for the spatiotemporal mapping of binding events, is presented. Electron beam nanolithography was used to fabricate 20 × 20 arrays of gold nanostructures atop glass coverslips. A single biotinylated array was used to measure the association kinetics of neutravidin to the surface by spectroscopically determining the fractional occupancy as a function of time. By regenerating the same array, a reliable comparison of the kinetics could be made between control samples and neutravidin concentrations ranging from 1 µM to 50 nM. CCD-based imagery of the array, taken simultaneously with the spectroscopic measurements, reveals the binding of neutravidin to the surface as manifested by enhanced scattering over the majority of the resonance peak. The temporal resolution of the LSPR imaging technique was 200 ms and the spatial resolution was 8 µm(2).

Identification of a potent and metabolically stable series of fluorinated diphenylpyridylethanamine-based cholesteryl ester transfer protein inhibitors.

A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described. Optimization of the urea moiety, particularly by incorporation of fluorine, is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.

The medicalization of addiction treatment professionals.

In a previous article, the authors described the changes initiated by recent health care legislation, and how those changes might affect the practice of medicine and the delivery of addiction services. This article reviews the same changes with respect to how they have the potential to change the practice activities of addiction physicians, addiction therapists, addiction counselors and addiction nurses, as well as the activities of administrators and service delivery financial personnel. Developments in delivery systems and the impact of those developments on professionals who work in addiction treatment are considered; current problems, potential solutions, and opportunities for clinicians under health reform are addressed. The goals envisioned for health system reform and the potential for realization of those goals via changes in addiction service delivery design and clinical practice are discussed.

The status of physician health programs in Wisconsin and north central states: a look at statewide and health systems programs.

There is increased recognition of the importance of physician health and the need to actively maintain and promote it. Attending to the health and well-being of medical clinicians is considered an important component of professionalism, and is important for the sustainability of safe, high-quality practice of medicine. This report highlights the importance of physician health programs, describes their history and evolution as well as the variability in program structure in various states, and reviews the present status of physician health resources, especially in Wisconsin. It gives an example of a program within a large, integrated health system and emphasizes the advantages of a statewide program.

Nicotine Addiction: A Burning Issue in Addiction Psychiatry.

Addressing nicotine addiction has been given a low priority, compared with other substance use disorders (SUDs), by the addiction treatment field. Persons with nicotine addiction are reluctant to attempt to stop using nicotine products-despite recognizing it to be a problem-because they are feeling discouraged by multiple past unsuccessful attempts at quitting. By understanding that discouragement is a frequent reason that these people are in Precontemplation and by using traditional clinical interventions applied to other SUDs, clinicians could achieve better overall treatment outcomes.

Specialized training on addictions for physicians in the United States.

In the United States accredited residency programs in addiction exist only for psychiatrists specializing in addiction psychiatry (ADP); nonpsychiatrists seeking training in addiction medicine (ADM) can train in nonaccredited "fellowships," or can receive training in some ADP programs, only to not be granted a certificate of completion of accredited training. Information about ADP residency programs has been tabulated, but it is not available for ADM fellowships. The authors conducted a national survey to compile information about the location, structure, curriculum, and other characteristics of active ADM fellowships. Of the 40 accredited ADP residency programs, 7 offered training in addiction to nonpsychiatrists. The authors identified 14 nonaccredited ADM fellowships. In 2009 and 2010, there were approximately 15 nonpsychiatrists in ADP programs and 25 in ADM fellowships. Clinical experiences included inpatient services, outpatient treatment services such as methadone maintenance or buprenorphine maintenance, and providing addiction consult services. The most common academic activities included weekly lectures and the teaching of medical students.

Language Matters: It Is Time We Change How We Talk About Addiction and its Treatment.

The way we communicate about addiction, its treatment, and treatment outcomes matters to individuals affected by addiction, their families, and communities. Stigmatizing language can worsen addiction-related stigma and outcomes. Although non-professional terminology may be used by individuals with addiction, the role of clinicians, educators, researchers, policymakers, and community and cultural leaders is to actively work toward destigmatization of addiction and its treatment, in part through the use of non-stigmatizing language. Role-modeling better approaches can help us move away from the inaccurate, outdated view of addiction as a character flaw or moral failing deserving of punishment, and toward that of a chronic disease requiring long-term treatment. Non-stigmatizing, non-judgmental, medically-based terminology and the adoption of person-first language can facilitate improved communication as well as patient access to and engagement with addiction care. Person-first language, which shifts away from defining a person through the lens of disease (eg, the term "a person with addiction" is recommended over the terms "addict" or "addicted patient"), implicitly acknowledges that a patient's life extends beyond a given disease. While such linguistic changes may seem subtle, they communicate that addiction, chronic pain and other diseases are only one aspect of a person's health and quality of life, and can promote therapeutic relationships, reduce stigma and health and disparities in addiction care. This article provides examples of stigmatizing terms to be avoided and recommended replacements to facilitate the dialogue about addiction in a more intentional, therapeutic manner.

Mindfulness-based relapse prevention for alcohol dependence: Findings from a randomized controlled trial.

OBJECTIVES: To assess the effects of mindfulness-based relapse prevention for alcohol dependence (MBRP-A) intervention on drinking and related consequences. METHODS: 123 alcohol-dependent adults in early recovery, recruited from outpatient treatment programs, were randomly assigned to MBRP-A (intervention plus usual-care; N = 64) or Control (usual-care-alone; N = 59) group. MBRP-A consisted of eight-weekly sessions and home practice. Outcomes were assessed at baseline, 8 weeks and 26 weeks (18 weeks post-intervention), and compared between groups using repeated measures analysis. RESULTS: Outcome analysis included 112 participants (57 MBRP-A; 55 Control) who provided follow-up data. Participants were 41.0 ±â€¯12.2 years old, 56.2% male, and 91% white. Prior to "quit date," they reported drinking on 59.4 ±â€¯34.8% (averaging 6.1 ±â€¯5.0 drinks/day) and heavy drinking (HD) on 50.4 ±â€¯35.5% of days. Their drinking reduced after the "quit date" (before enrollment) to 0.4 ±â€¯1.7% (HD: 0.1 ±â€¯0.7%) of days. At 26 weeks, the MBRP-A and control groups reported any drinking on 11.5 ±â€¯22.5% and 5.9 ±â€¯11.6% of days and HD on 4.5 ±â€¯9.3% and 3.2 ±â€¯8.7% of days, respectively, without between-group differences (ps ≥ 0.05) in drinking or related consequences during the follow-up period. Three MBRP-A participants reported "relapse," defined as three-consecutive HD days, during the study. Subgroup analysis indicated that greater adherence to session attendance and weekly home practice minutes were associated with improved outcomes. CONCLUSIONS: MBRP-A as an adjunct to usual-care did not show to improve outcomes in alcohol-dependent adults in early recovery compared to usual-care-alone; a return to drinking and relapse to HD were rare in both groups. However, greater adherence to MBRP-A intervention may improve long-term drinking-related outcomes.

Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Amination of heterocyclic compounds with o-benzoylhydroxylamine derivatives.

The N-amination of heterocyclic compounds 1a-k with O-benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior alternative to existing N-amination methods. A structure-reactivity relationship study was performed on variously substituted O-benzoylhydroxylamine derivatives, leading to the discovery of the novel and more efficient aminating reagents 5h and 5i.

Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding.

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.

Blood glucose levels and cortical thinning in cognitively normal, middle-aged adults.

Type II diabetes mellitus (DM) increases risk for cognitive decline and is associated with brain atrophy in older demented and non-demented individuals. We investigated (1) the cross-sectional association between fasting blood glucose level and cortical thickness in a sample of largely middle-aged, cognitively normal adults, and (2) whether these associations were modified by genes associated with both lipid processing and dementia. To explore possible modifications by genetic status, we investigated the interaction between blood glucose levels and the apolipoprotein E (APOE) ε4 allele and the translocase of the outer mitochondrial membrane (TOMM) 40 '523 genotype on cortical thickness. Cortical thickness measures were based on mean thickness in a subset of a priori-selected brain regions hypothesized to be vulnerable to atrophy in Alzheimer's disease (AD) (i.e., 'AD vulnerable regions'). Participants included 233 cognitively normal subjects in the BIOCARD study who had a measure of fasting blood glucose and cortical thickness measures, quantified by magnetic resonance imaging (MRI) scans. After adjustment for age, sex, race, education, depression, and medical conditions, higher blood glucose was associated with thinner parahippocampal gyri (B=-0.002; 95% CI -0.004, -0.0004) and temporal pole (B=-0.002; 95% CI -0.004, -0.0001), as well as reduced average thickness over AD vulnerable regions (B=-0.001; 95% CI -0.002, -0.0001). There was no evidence for greater cortical thinning in ε4 carriers of the APOE gene or in APOE ε3/3 individuals carrying the TOMM40 VL/VL genotypes. When individuals with glucose levels in the diabetic range (≥126mg/dL), were excluded from the analysis, the associations between glucose levels and cortical thickness were no longer significant. These findings suggest that glucose levels in the diabetic range are associated with reduced cortical thickness in AD vulnerable regions as early as middle age.

Total synthesis of (-)- and ent-(+)-vindoline.

[reaction: see text] Two exceptionally concise total syntheses of (-)- and ent-(+)-vindoline are detailed enlisting a diastereoselective tandem [4 + 2]/[3 + 2] cycloaddition of a 1,3,4-oxadiazole. The unique reaction cascade assembles the fully functionalized pentacyclic ring system of vindoline in a single step that forms four C-C bonds and three rings while introducing all requisite functionality and setting all six stereocenters within the central ring including three contiguous and four total quaternary centers.

Safety and efficacy of Implanon, a single-rod implantable contraceptive containing etonogestrel.

OBJECTIVES: The safety and efficacy of a single-rod implantable contraceptive containing etonogestrel (Implanontrade mark) were investigated in a multicenter clinical trial. STUDY DESIGN: Sexually active American women (N=330) with apparently normal menstrual cycles used the implant for up to 2 years. All subjects recorded bleeding and/or spotting daily in a diary. Safety was assessed through adverse experiences (AEs), laboratory tests and physical and gynecologic examinations. RESULTS: Total exposure was 474 woman-years (6186 cycles), and 68% of subjects had at least 1 year of exposure. No pregnancies occurred. The most common bleeding pattern observed throughout the study was infrequent bleeding, defined as less than three episodes of bleeding in a reference period (excluding amenorrhea). The least common pattern was frequent bleeding, defined as more than five episodes of bleeding in a reference period. Infrequent, prolonged and frequent bleeding patterns were most common early in the study and declined thereafter. During the 3-month Reference Periods 2-8 (Months 4-24), the incidence of amenorrhea ranged from 14% to 20%. Forty-three subjects (13%) withdrew from the study because of bleeding pattern changes and 76 subjects (23%) discontinued because of other AEs. Other common AEs leading to discontinuation, besides bleeding irregularities, were emotional lability (6.1%), weight increase (3.3%), depression (2.4%) and acne (1.5%). Use of Implanon (etonogestrel subdermal implant, referred to herein as ENG implant) for up to 2 years had no clinically significant effects on laboratory parameters, physical and pelvic examinations, vital signs or body mass index. The average length of time required for ENG implant insertion and that for removal were 0.5 and 3.5 min, respectively, and all the procedures were uncomplicated. The return to normal menstrual cycles and fertility was rapid after removal. CONCLUSIONS: Implanon is a safe, highly effective and rapidly reversible new method of contraception.