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Objective: The New York City Mental Health Care Monitoring Initiative uses Medicaid claims data to identify individuals with serious mental illness who are experiencing or at risk for gaps in services. In this study the authors assessed whether proposed service use algorithms accurately identified such individuals.Methods: A random sample of 500 individuals with serious mental illness was identified. Individuals belonged to specific high-need cohorts and met predefined claims-based criteria for potential service gaps. Clinical staff initiated reviews with prior service providers for 230 individuals.Results: Over a two-week period staff completed reviews for 188 cases (88%). In 66 cases (35%) the individual was fully engaged in care; 84 (45%) had a recent episode of disengagement that was appropriately addressed, and 38 (20%) were not receiving adequate services.Conclusions: The proposed service use algorithms successfully identified high-need individuals with serious mental illness at risk for gaps in services. [ABSTRACT FROM AUTHOR]

Individuals with obsessive-compulsive disorder (OCD), a chronic and disabling psychiatric disorder, experience high rates of occupational impairment. OCD symptoms commonly affect individuals' vocational aspirations and result in disability and the need for financial support, problems that are not addressed by current clinical practice guideline recommendations for treating OCD. This Open Forum highlights the need to address occupational impairment caused by OCD and makes the case for formally evaluating whether evidence-based supported employment can help individuals with OCD find and succeed in meaningful work., Competing Interests: Dr. Simpson reports receiving royalties from Cambridge University Press and UpToDate and a stipend from the American Medical Association for serving as associate editor of JAMA Psychiatry. The other authors report no financial relationships with commercial interests.

Helicases, classified into six superfamilies, are mechanoenzymes that utilize energy derived from ATP hydrolysis to remodel DNA and RNA substrates. These enzymes have key roles in diverse cellular processes, such as translation, ribosome assembly, and genome maintenance. Helicases with essential functions in certain cancer cells have been identified, and helicases expressed by many viruses are required for their pathogenicity. Therefore, helicases are important targets for chemical probes and therapeutics. However, it has been very challenging to develop chemical inhibitors for helicases, enzymes with high conformational dynamics. We envisioned that electrophilic "scout fragments", which have been used in chemical proteomic studies, could be leveraged to develop covalent inhibitors of helicases. We adopted a function-first approach, combining enzymatic assays with enantiomeric probe pairs and mass spectrometry, to develop a covalent inhibitor that selectively targets an allosteric site in SARS-CoV-2 nsp13, a superfamily-1 helicase. Further, we demonstrate that scout fragments inhibit the activity of two human superfamily-2 helicases, BLM and WRN, involved in genome maintenance. Together, our findings suggest an approach to discover covalent inhibitor starting points and druggable allosteric sites in conformationally dynamic mechanoenzymes.

Objective: With a lifetime U.S. prevalence of 2.3%, obsessive-compulsive disorder (OCD) is a chronic condition often producing reduced quality of life and disability when left untreated. Little is known about the prevalence or treatment of diagnosed OCD in public behavioral health systems., Methods: Using a claims analysis of 2019 New York State Medicaid data (N=2,245,084 children; N=4,274,100 adults), the authors investigated the prevalence and characteristics of children and adults with OCD. The authors also examined whether these individuals received treatment with medication or psychotherapy., Results: The prevalence of OCD was 0.2% among children and 0.3% among adults. Fewer than half of children (40.0%) and adults (37.5%) received U.S. Food and Drug Administration-approved medications (with or without psychotherapy); another 19.4% of children and 11.0% of adults received 45- or 60-minute psychotherapy alone., Conclusions: These data demonstrate the need for public behavioral health systems to increase their capacity to identify and treat OCD., Competing Interests: In the past 3 years, Dr. Simpson has received research support from Biohaven, royalties from Cambridge University Press and UpToDate, and a stipend from the American Medical Association for serving as the associate editor of JAMA Psychiatry. The other authors report no financial relationships with commercial interests.

Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.

Nearly half of all pregnancies are unintended; thus, existing family planning options are inadequate. For men, the only choices are condoms and vasectomy, and most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months of continuous pretreatment. Here, we provide proof-of-concept for an innovative strategy for on-demand contraception, where a man would take a birth control pill shortly before sex, only as needed. Soluble adenylyl cyclase (sAC) is essential for sperm motility and maturation. We show a single dose of a safe, acutely-acting sAC inhibitor with long residence time renders male mice temporarily infertile. Mice exhibit normal mating behavior, and full fertility returns the next day. These studies define sAC inhibitors as leads for on-demand contraceptives for men, and they provide in vivo proof-of-concept for previously untested paradigms in contraception; on-demand contraception after just a single dose and pharmacological contraception for men., (© 2023. The Author(s).)

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO 3 - )-regulated soluble adenylyl cyclase (sAC; ADCY10) is uniquely essential in sperm for reproduction. For this reason, sAC has been proposed as a potential therapeutic target for non-hormonal contraceptives for men. Here, we describe key sAC-focused in vitro assays to identify and characterize sAC inhibitors for therapeutic use. The affinity and binding kinetics of an inhibitor can greatly influence in vivo efficacy, therefore, we developed improved assays for assessing these efficacy defining features., Competing Interests: JB and LL have licensed commercialization of a panel of monoclonal antibodies directed against sAC. CS, JB, LL, and employees of the Tri-Institutional Therapeutics Discovery Institute (TDI) may benefit from the further development and licensure of molecules described herein. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rossetti, Ferreira, Ghanem, Buck, Steegborn, Myers, Meinke, Levin and Buck.)

The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.

Obsessive-compulsive disorder (OCD), a frequently disabling disorder characterized by distressing thoughts and behaviors, often goes undetected, or individuals with this disorder do not receive evidence-based care. Educating clinicians and individuals with OCD and their families about OCD is a necessary first step to improving quality of care. This Open Forum describes the creation of a workforce development program named Improving Providers' Assessment, Care Delivery, and Treatment of OCD (IMPACT-OCD). This program used implementation science methods to engage stakeholders, assess practice determinants, and develop a multifaceted training strategy to raise awareness of OCD and to improve clinician knowledge and skills in OCD care.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC 50 s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Obsessive-compulsive disorder (OCD) can be a chronic and disabling illness with a lifetime prevalence of 2%, twice that of schizophrenia. Although effective treatments exist, OCD often remains underdetected and undertreated., Methods: The authors performed a scoping review of the literature (of articles in PubMed and PsycINFO published from January 1, 2000, to February 1, 2020) to define gaps in OCD diagnosis and treatment among U.S. adults. Interventions at the patient, clinician, and health care system levels used to address these gaps are described, and promising approaches from around the world are highlighted., Results: Of 102 potential studies identified in the search, 27 (including five non-U.S. studies) were included. The studies revealed that lack of clinician and patient knowledge about OCD and misdiagnosis contributes to its underdetection. Suboptimal prescribing of selective serotonin reuptake inhibitor medications and limited use of exposure and response prevention, as a first-line psychotherapy, contribute to OCD undertreatment. Digital health technologies show promise in increasing OCD detection and delivery of evidence-based care and in ensuring continuity of care (including during the COVID-19 pandemic)., Conclusions: Given the significant rates of disability, morbidity, and mortality associated with OCD, addressing gaps in OCD care will reduce the U.S. burden of mental illness. Further research is needed to determine how the use of digital health technologies can increase the detection and management of OCD.

The oncoprotein and Parkinson's disease-associated enzyme DJ-1/PARK7 has emerged as a promiscuous deglycase that can remove methylglyoxal-induced glycation adducts from both proteins and nucleotides. However, dissecting its structural and enzymatic functions remains a challenge due to the lack of potent, specific, and pharmacokinetically stable inhibitors targeting its catalytic site (including Cys106). To evaluate potential drug-like leads against DJ-1, we leveraged its deglycase activity in an enzyme-coupled, fluorescence lactate-detection assay based on the recent understanding of its deglycation mechanism. In addition, we developed assays to directly evaluate DJ-1's esterase activity using both colorimetric and fluorescent substrates. The resulting optimized assay was used to evaluate a library of potential reversible and irreversible DJ-1 inhibitors. The deglycase activity-oriented screening strategy described herein establishes a new platform for the discovery of potential anti-cancer drugs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors., Competing Interests: The authors declare the following competing financial interest(s): Authors are current or former employees of Merck & Co., Inc., Kenilworth, NJ, USA and potentially own stock and/or hold stock options in the Company., (© 2021 American Chemical Society.)

An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques. The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

HIV persistence in latently infected, resting CD4 + T cells is broadly considered a barrier to eradicate HIV. Activation of the provirus using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs has been touted as a promising therapeutic approach. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. Several clinical HDAC inhibitors had been examined as LRAs, which induced HIV activation in vitro and in vivo. Here we report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells. The SAR led to the discovery of a highly selective class I HDAC inhibitor 10 with excellent potency. HDACi 10 induces the HIV gag P24 protein in patient latent CD4 + T cells., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

The New York State Medicaid program is pursuing reforms that would shift reimbursement from fee-for-service to value-based models. Behavioral health populations and services are key to these reforms, but important gaps exist in the breadth and relevance of available quality measures for the behavioral health field. This column describes how the state addressed these gaps by using both inter- and intra-agency collaborations. As part of this effort, the state convened a panel of consultants, including academics, providers, and consumers, to develop a behavioral health quality measurement agenda. Panel recommendations and ongoing partnerships are described as a model for states considering similar value-based reform initiatives.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic., Competing Interests: All authors are or were employees of Merck & Co., Inc., Kenilworth, NJ, USA, and may own shares of company stock. Merck & Co., Inc., Kenilworth, NJ, USA, provisional patent applications for LA1, LA2, SA1 and SA2 and related AMPK activators were filed on 23 February 2012 (WO2012116145; Novel Cyclic Azabenzimidazole derivatives useful as anti-diabetic agents). All of the authors employed by Merck & Co., Inc., Kenilworth, NJ, USA, have a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cognitive-behavioral therapy (CBT), consisting of exposure and response prevention (EX/RP), is both efficacious and preferred by patients with obsessive-compulsive disorder (OCD), yet few receive this treatment in practice. This study describes the implementation of an Internet-based CBT program (ICBT) developed in Sweden in individuals seeking OCD treatment in New York. After translating and adapting the Swedish ICBT for OCD, we conducted an open trial with 40 adults with OCD. Using the RE-AIM implementation science framework, we assessed the acceptability, feasibility, and effectiveness of ICBT. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the primary outcome measure. Of 40 enrolled, 28 participants completed the 10-week ICBT. In the intent-to-treat sample (N = 40), Y-BOCS scores decreased significantly over time (F = 28.12, df = 2, 49, p < . 001). Depressive severity (F = 5.87, df = 2, 48, p < . 001), and quality of life (F = 12.34, df = 2, 48, p < . 001) also improved. Sensitivity analyses among treatment completers (N = 28) confirmed the intent-to-treat results, with a large effect size for Y-BOCS change (Cohen's d = 1.38). ICBT took less time to implement than face-to face EX/RP and participants were very to mostly satisfied with ICBT. On a par with results in Sweden, the adapted ICBT program reduced OCD and depressive symptoms and improved quality of life among individuals with moderate to severe OCD. Given its acceptability and feasibility, ICBT deserves further study as a way to increase access to CBT for OCD in the United States., (Copyright © 2017. Published by Elsevier Ltd.)

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of β1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving β2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration., Competing Interests: The authors declare no competing financial interest.

We have developed and validated label-free, liquid chromatography-mass spectrometry (LC-MS)-based equilibrium direct and competition binding assays to quantitate small-molecule antagonist binding to recombinant human and mouse BLT1 receptors expressed in HEK 293 cell membranes. Procedurally, these binding assays involve (1) equilibration of the BLT1 receptor and probe ligand, with or without a competitor; (2) vacuum filtration through cationic glass fiber filters to separate receptor-bound from free probe ligand; and (3) LC-MS analysis in selected reaction monitoring mode for bound probe ligand quantitation. Two novel, optimized probe ligands, compounds 1 and 2 , were identified by screening 20 unlabeled BLT1 antagonists for direct binding. Saturation direct binding studies confirmed the high affinity, and dissociation studies established the rapid binding kinetics of probe ligands 1 and 2 . Competition binding assays were established using both probe ligands, and the affinities of structurally diverse BLT1 antagonists were measured. Both binding assay formats can be executed with high specificity and sensitivity and moderate throughput (96-well plate format) using these approaches. This highly versatile, label-free method for studying ligand binding to membrane-associated receptors should find broad application as an alternative to traditional methods using labeled ligands.

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia.

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic β-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice., (Copyright © 2016. Published by Elsevier Ltd.)

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic β-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia., (Copyright © 2016. Published by Elsevier Ltd.)

Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2 NI ) and R531G (AMPKγ2 RG ), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2 NI or AMPKγ2 RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2 NI or AMPKγ2 RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2 NI and AMPKγ2 RG , respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2 NI or AMPKγ2 RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2 WT mice, AMPKγ2 NI and AMPKγ2 RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2 RG but not AMPKγ2 NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2 NI and AMPKγ2 RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2 RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Scant evidence exists in the literature for best practices in training assertive community treatment (ACT) teams to deliver highly effective services to consumers. This column describes a blended training curriculum, which includes both face-to-face and distance learning strategies, developed by the ACT Training Institute in New York State to meet the ongoing training needs of teams across New York State. Data on training uptake, which has steadily increased over time, are reported. The role of the state is crucial in driving adoption of training activities. The column also describes how the ACT Training Institute uses fidelity and outcome data to identify training needs.

This review provides a concise summary for state of the art, moderate to high throughput in vitro technologies being employed to study drug-target binding kinetics. These technologies cover a wide kinetic timescale spanning up to nine orders of magnitude from milliseconds to days. Automated stopped flow measures transient and (pre)steady state kinetics from milliseconds to seconds. For seconds to hours timescale kinetics we discuss surface plasmon resonance-based biosensor, global progress curve analysis for high throughput kinetic profiling of enzyme inhibitors and activators, and filtration plate-based radioligand or fluorescent binding assays for receptor binding kinetics. Jump dilution after pre-incubation is the preferred method for very slow kinetics lasting for days. The basic principles, best practices and simulated data for these technologies are described. Finally, the application of a universal label-free technology, liquid chromatography coupled tandem mass spectrometry (LC/MS/MS), is briefly reviewed. Select literature references are highlighted for in-depth understanding. A new reality is dawning wherein binding kinetics is an integral and routine part of mechanism of action elucidation and translational, quantitative pharmacology for drug discovery.

Topic: This column describes how public partners can help incentivize participation in training. Specifically, a state mental health agency and its implementation center applied financial and nonfinancial incentives to encourage participation in training and implementation supports., Purpose: Although training is not sufficient to change practice, it is a necessary first step in implementing evidence-based treatments. Finding ways to incentivize participation, particularly strategies with minimal resource involvement, is important for the psychiatric rehabilitation workforce and cash-strapped public systems., Sources Used: This description draws from published material and experiences from New York State., Conclusions and Implications for Practice: Engaging public partners to incentivize training can significantly increase participation in training. Incentive programs exist that do not require additional funding-an important consideration, given the fiscal climate for most public payers., ((c) 2016 APA, all rights reserved).)

This column focuses on use of learning collaboratives by the Center for Practice Innovations to help programs implement the evidence-based individual placement and support model of supported employment in New York State. These learning collaboratives use fidelity and performance indicator data to drive the development of program-specific individualized quality improvement plans. As of 2014, 59 (69%) of 86 eligible programs have joined the initiative. Programs are achieving employment outcomes for consumers on par with national benchmarks, along with improved fidelity.

Objective: The study determined rates of reengagement in services for individuals with serious mental illness who had discontinued services., Methods: As part of a quality assurance program in New York City involving continuous review of Medicaid claims and other administrative data, clinician care monitors identified 2,834 individuals with serious mental illness who were apparently in need of care but disengaged from services. The care monitors reviewed monthly updates of Medicaid claims, encouraged outreach from providers who had previously worked with identified individuals, and determined whether individuals had reengaged in services., Results: Reengagement rates over a 12-month follow-up period were low, particularly for individuals who had been incarcerated or for whom no service provider was available to provide outreach., Conclusions: Subgroups of disengaged individuals with serious mental illness have different rates of reengagement. Active outreach by providers might benefit some, but such targeting is inefficient when the individual cannot be located.

This study examined whether Medicaid claims and other administrative data could identify high-need individuals with serious mental illness in need of outreach in a large urban setting. A claims-based notification algorithm identified individuals belonging to high-need cohorts who may not be receiving needed services. Reviewers contacted providers who previously served the individuals to confirm whether they were in need of outreach. Over 10,000 individuals set a notification flag over 12-months. Disengagement was confirmed in 55 % of completed reviews, but outreach was initiated for only 30 %. Disengagement and outreach status varied by high-need cohort.

This column describes the Center for Practice Innovations (CPI), which was created in 2007 by the New York State Office of Mental Health and the Department of Psychiatry at Columbia University. CPI uses innovative approaches to build stakeholder collaborations, develop and maintain practitioners' expertise, and build agency infrastructures that support implementing and sustaining evidence-based practices. CPI's five core initiatives provide training in co-occurring mental and substance use disorders, assertive community treatment, supported employment and education, wellness self-management, and treatment of first-episode psychosis. Central to CPI's activities are award-winning training modules, statewide learning collaboratives, and use of a learning management system.

Mental health authorities across the country face numerous challenges in developing effective and practical strategies to adopt and sustain research-supported and stakeholder-endorsed mental health practices. This column describes how an academic center assists a mental health authority in making policy decisions by the use of advisory panels of multiple stakeholders, including members of the research community, advocacy organizations, service providers, and consumers. An advisory panel that focused on services involving family members for adults with serious mental health problems serves as a case example.

Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.

Public mental health authorities have access to large administrative databases. Advances in information technology now make it possible to use secondary analyses of these data to inform policy and clinical interventions. New York City and State mental health authorities developed an initiative using Medicaid claims and other administrative data to identify individuals with serious mental illness living in New York City (NYC) who are at risk of lapses in care. The NYC Mental Health Care Monitoring Initiative represents one of the first efforts to create "evidence-based policy." The authors describe the initiative's background, development, and key collaborations.

beta-D-Fructose-2,6-bisphosphate (Fru-2,6-P(2)) is an important regulator of eukaryotic glucose homeostasis, functioning as a potent activator of 6-phosphofructo-1-kinase and inhibitor of fructose-1,6-bisphosphatase. Pharmaceutical manipulation of intracellular Fru-2,6-P(2) levels, therefore, is of interest for the treatment of certain diseases, including diabetes and cancer. [2-(32)P]Fru-2,6-P(2) has been the reagent of choice for studying the metabolism of this effector molecule; however, its short half-life necessitates frequent preparation. Here we describe a convenient, economical, one-pot enzymatic preparation of high-specific-activity tritium-labeled Fru-2,6-P(2). The preparation involves conversion of readily available, carrier-free d-[6,6'-(3)H]glucose to [6,6'-(3)H]Fru-2,6-P(2) using hexokinase, glucose-6-phosphate isomerase, and 6-phosphofructo-2-kinase. The key reagent in this preparation, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase from human liver, was produced recombinantly in Escherichia coli and purified in a single step using an appendant C-terminal hexa-His affinity tag. Following purification by anion exchange chromatography using triethylammonium bicarbonate as eluant, radiochemically pure [6,6'-(3)H]Fru-2,6-P(2) having a specific activity of 50 Ci/mmol was obtained in yields averaging 35%. [6,6'-(3)H]Fru-2,6-P(2) serves as a stable, high-specific-activity substrate in a facile assay capable of detecting fructose-2,6-bisphosphatase in the range of 10(-14) to 10(-15) mol, and it should prove to be useful in many studies of the metabolism of this important biofactor., (Copyright 2010 Elsevier Inc. All rights reserved.)

Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.

The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.

A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.

The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model.

Unsporulated oocysts of the protozoan parasite Eimeria tenella contain high levels of mannitol, which is thought to be the principal energy source for the process of sporulation. Biosynthesis and utilization of this sugar alcohol occurs via a metabolic pathway known as the mannitol cycle. Here, results are presented that suggest that 3-nitrophenyl disulfide (nitrophenide, Megasul), an anticoccidial drug commercially used in the 1950s, inhibits mannitol-1-phosphate dehydrogenase (M1PDH), which catalyzes the committed enzymatic step in the mannitol cycle. Treatment of E. tenella-infected chickens with nitrophenide resulted in a 90% reduction in oocyst shedding. The remaining oocysts displayed significant morphological abnormalities and were largely incapable of further development. Nitrophenide treatment did not affect parasite asexual reproduction, suggesting specificity for the sexual stage of the life cycle. Isolated oocysts from chickens treated with nitrophenide exhibited a dose-dependent reduction in mannitol, suggesting in vivo inhibition of parasite mannitol biosynthesis. Nitrophenide-mediated inhibition of MIPDH was observed in vitro using purified native enzyme. Moreover, MIPDH activity immunoprecipitated from E. tenella-infected cecal tissues was significantly lower in nitrophenide-treated compared with untreated chickens. Western blot analysis and immunohistochemistry showed that parasites from nitrophenide-treated and untreated chickens contained similar enzyme levels. These data suggest that nitrophenide blocks parasite development at the sexual stages by targeting M1PDH. Thus, targeting of the mannitol cycle with drugs could provide an avenue for controlling the spread of E. tenella in commercial production facilities by preventing oocyst shedding.