Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors.

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure-activity relationship (SAR) points for delivery of potent ACC inhibitors.

Exploring the Progressive Use of Performance Enhancing Substances by High-Performance Athletes.

Background: Given implications associated with the use of performance-enhancing substances (PESs), stakeholders must remain informed about usage precipitants and anticipate conditions signaling athlete vulnerability to hazardous exposures. Objectives: To gain deeper qualitative insight into high-level athlete PES usage; explore the variables leading them to escalate their PES use regimens; reveal PES experiences during their careers and, unlike other studies, not to focus exclusively on "doping" as measured by the use of WADA-banned substances. Methods: A macro life course-based framework from which the data could emerge through a thematic coding analysis was utilized. Sixteen narrative life course histories of recently retired high-performance athletes report on the factors impelling their escalation in PES use, including for some, the first use of banned PES. Results: Informant reports, thematically coded, reveal performance maximization urgency to be a central factor in escalating PES use, driven by four variables: Requirements, Opportunities, Influencers and Outcomes. These variables each comprise two key components that stimulate an urgency ecosystem affecting an athlete's proximity to an escalation threshold. Conclusions/Importance: Such a comprehensive investigation of PES use precipitants has not previously been undertaken. Advances in PES use were instantiated by a substantive, sometimes radical and often sudden increase in urgency to improve performance related to output requirements, specific demands, knowledge and access, timing windows, the competitive landscape, loyalty to coaches, efficiency expectations and likelihood of detection. This study informs incremental models of doping, the use of which is encouraged in order to analyze life course narratives to better understand athlete behaviors.

Cognitive Enhancing Drugs in Sport: Current and Future Concerns.

BACKGROUND: Sporting authorities and policy makers have warned of a radical increase in the availability and use of so-called 'smart' drugs, which putatively deliver cognitive enhancements in the form of improved focus, concentration, alertness, and rapid decision-making. Although the potential for health risks is well documented when it comes to performance enhancing drugs in sport, the health implications of cognitive enhancing drugs (CEDs) remain unclear. Objectives: This article aims to provide a foundational understanding about CEDs and their application in sport. It considers what little is known about the types, nature, impact, and implications of their use for athletes and sport policy. Method: A narrative literature review was undertaken to ascertain the emerging role of CEDs beyond their clinical use to treat prescribed disorders, including the limited studies in the sporting domain. This review also considered literature pertinent to the impact of CEDs in sport and the challenges for sport policy. Results: Given the prospects of negative health impacts, policy-makers interested in preventing and controlling the use of CEDs, as well as reducing harm to athletes at all levels of performance, need guidance. This article highlights multi-faceted concerns and shines a spotlight on key issues for sporting bodies to consider regarding the critical impact that widespread use and adoption of these substances might entail. Conclusion: While the World Anti-Doping Agency (WADA) is seemingly awake to the threat posed, actions to circumvent the spread of CEDs throughout sport are nascent and require greater understanding and attention.

Two Scalable Syntheses of (S)-2-Methylazetidine.

Two orthogonal routes for preparing (S)-2-methylazetidine as a bench stable, crystalline (R)-(-)-CSA salt are presented. One route features the in situ generation and cyclization of a 1,3-bis-triflate to form the azetidine ring, while the second route involves chemoselective reduction of N-Boc azetidine-2-carboxylic acid. Both sequences afford the desired product in good overall yields (61% and 49%) and high enantiomeric excess (>99% ee), avoid column chromatography, and are suitable for the large-scale production of this material.

The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro[4.5]decane) Ring Systems.

The synthesis of a series of pharmaceutically important N-protected methyl-substituted spirocyclic piperidine-azetidine (2,7-diazaspiro[3.5]nonane) and spirocyclic piperidine-pyrrolidine (2,8-diazaspiro[4.5]decane) ring systems was developed. These motifs contain two differentiated sites (protected secondary amines) to allow for further functionalization via reductive amination, amidation, or other chemistry. The methyl-substituted spiroazetidine ring systems were accessed using nitrile lithiation/alkylation chemistry while the methyl-substituted spiropyrrolidines were synthesized by 1,4-addition reactions with nitroalkanes, followed by reduction and cyclization. These conditions were then scaled for the synthesis of 1-methyl spirocyclic piperidine-pyrrolidine with a classical resolution of the product using a tartaric acid derivative to isolate a single enantiomer.

Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.

Why the war on drugs in sport will never be won.

Recent exposes of drug use in sports suggest that doping might be more problematic than doping-control test results reveal. A zero-tolerance (ZT) model, which aims to eliminate the use, has dominated the thinking of sport's policy makers over the last 15 years. In light of the limitations associated with ZT-based policy, we propose an alternative policy, one based on controlled use and harm reduction principles. We argue that substance control policies underpinned by harm reduction (HR) principles of social utility and public value will deliver superior social outcomes. First, a harm reduction approach better accommodates the competitive realities of sports and the impact of elite sports' emphasis on performance at all costs. Second, HR prioritises athlete welfare over sport and brand reputation. Finally, while appreciating the regulatory and risk management responsibilities of sports' governing bodies, the HR model offers greater space to the athlete's right to privacy, and right to personal autonomy.

Palladium-Catalyzed Synthesis of (Hetero)Aryl Alkyl Sulfones from (Hetero)Aryl Boronic Acids, Unactivated Alkyl Halides, and Potassium Metabisulfite.

A palladium-catalyzed one-step synthesis of (hetero)aryl alkyl sulfones from (hetero)arylboronic acids, potassium metabisulfite, and unactivated or activated alkylhalides is described. This transformation is of broad scope, occurs under mild conditions, and employs readily available reactants. A stoichiometric experiment has led to the isolation of a catalytically active dimeric palladium sulfinate complex, which was characterized by X-ray diffraction analysis.

Renal Location Within the Retroperitoneum in Various Body Positions Using Magnetic Resonance Imaging: Implications for Percutaneous Nephrostolithotomy.

OBJECTIVES: To assess the difference in cranio-caudal renal position in both the supine and prone position, as well as the effect of arm position on renal location, using magnetic resonance imaging in subjects with BMI <30. METHODS: In a prospective IRB approved trial, healthy subjects underwent magnetic resonance imaging in the supine, prone position with arms at the side, and prone position with arms up using vertically placed towel bolsters. Images were obtained with end expiration breath holds. Distances between the kidney and other anatomical landmarks, including the diaphragm (KDD), top of the L1 vertebra (KVD) and lower edge of the 12th rib (KRD), were recorded. Nephrostomy tract length (NTL) and other measures for visceral injury were also assessed. Wilcoxon signed rank test was used for analysis (P < .05). RESULTS: Ten subjects (5 male, 5 female) with median age of 29 years and BMI of 24 kg/m2 were imaged. Right KDD was not significantly different between positions, but KRD and KVD noted significant cephalad movement when prone, as compared to supine. Left KDD noted caudal movement with prone positioning with no difference in KRD or KVD. Arm position did not affect any measurements. Right lower NTL was shorter when prone. CONCLUSIONS: In subjects with BMI < 30, prone positioning led to significant cephalad right renal movement, but not left renal movement. Arm position had no effect on anticipated renal position. Preoperative end expiration supine CT may reliably predict left kidney location and be used to improve preoperative counseling and/or surgical planning.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Urethroplasty: a geographic disparity in care.

PURPOSE: Urethroplasty is the gold standard for urethral strictures but its geographic prevalence throughout the United States is unknown. We analyzed where and how often urethroplasty was being performed in the United States compared to other treatment modalities for urethral stricture. MATERIALS AND METHODS: De-identified case logs from the American Board of Urology were collected from certifying/recertifying urologists from 2004 to 2009. Results were categorized by ZIP codes to determine the geographic distribution. RESULTS: Case logs from 3,877 urologists (2,533 recertifying and 1,344 certifying) were reviewed including 1,836 urethroplasties, 13,080 urethrotomies and 19,564 urethral dilations. The proportion of urethroplasty varied widely among states (range 0% to 17%). The ratio of urethroplasty-to-urethrotomy/dilation also varied widely from state to state, but overall 1 urethroplasty was performed for every 17 urethrotomies or dilations performed. Certifying urologists were 3 times as likely to perform urethroplasty as recertifying urologists (12% vs 4%, respectively, p<0.05). Urethroplasties were performed more commonly in states with residency programs (mean 5% vs 3%). Some states reported no urethroplasties during the observation period (Vermont, North Dakota, South Dakota, Maine and West Virginia). CONCLUSIONS: To our knowledge this is the first report on the geographic distribution of urethroplasty for urethral stricture disease. There are large variations in the rates of urethroplasty performed throughout the United States, indicating a disparity of care, especially for those regions in which few or no urethroplasties were reported. This disparity may decrease with time as younger certifying urologists are performing 3 times as many urethroplasties as older recertifying urologists.

Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors.

The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.

Body perceptions and health behaviors in an online bodybuilding community.

In this article we explore the social constructions, body perceptions, and health experiences of a serious recreational and competitive bodybuilder and powerlifter community. Data were obtained from a discussion forum appearing within an online community dedicated to muscular development. Forum postings for a period of 36 months were transposed to QSR NVivo, in which a narrative-based analytical method employing Gee's coding approach was employed. We used a priori codes based on Bourdieu's multipronged conceptual categories of social field, habitus, and capital accumulation as a theoretical frame. Our results expose an extreme social reality held by a devoted muscle-building community with a fanatical obsession with muscular hypertrophy and any accouterment helpful in its acquisition, from nutrition and supplements to training regimes and anabolic androgenic substances. Few health costs were considered too severe in this muscular meritocracy, where the strong commanded deference and the massive dominated the social field.

Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls.

Heteroaromatic biaryls are core scaffolds found in a plethora of pharmaceuticals; however, their direct synthesis by the Suzuki cross-coupling is limited to heteroaromatic halide starting materials. Here, we report a direct synthesis of diverse nitrogen-containing heteroaromatic biaryls by Pd-catalyzed decarbonylative Suzuki cross-coupling of widely available heterocyclic carboxylic acids with arylboronic acids. The practical and modular nature of this cross-coupling enabled the straightforward preparation of >45 heterobiaryl products using pyridines, pyrimidines, pyrazines, and quinolines in excellent yields. We anticipate that the modular nature of this protocol will find broad application in medicinal chemistry and drug discovery research.

Synthesis of α-Heteroaryl Propionic Esters by Palladium-Catalyzed α-Heteroarylation of Silyl Ketene Acetals.

A practical and efficient synthesis of α-heteroaryl propionic esters is developed by employing palladium-catalyzed α-heteroarylation of silyl ketene acetals, forming a wide variety of α-heteroaryl propionic esters with various substituents and functionalities in high yields. The success of this transformation is credited to the development of the bulky P,P═O ligand. The method has provided an efficient synthesis of α-heteroaryl propionic acids.

Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting.

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.

An examination of how alcohol brands use sport to engage consumers on social media.

INTRODUCTION AND AIMS: To examine how alcohol brands use sport in their communication activities on social media. Despite extensive research exploring alcohol advertising and sponsorship through sport, minimal attention has been given to digital platforms. DESIGN AND METHODS: This study undertakes a qualitative content analysis to examine the social media activity of alcohol brands sponsoring the three largest spectator sports in Australia: Australian rules football, rugby league and cricket. RESULTS: Four sport-related social media strategies are identified through which alcohol brands solicit interaction with consumers, often involving co-creation of content and social activation. These strategies act as 'calls to action' and through the association of sport and alcohol encourage consumers to engage in competition, collaboration, celebration and consumption. These strategies are further strengthened by communications which draw upon themes of identity and camaraderie to resonate with the consumer. DISCUSSION AND CONCLUSIONS: Sport-linked social media strategies utilised by alcohol brands extend beyond just promoting their product. They seek higher levels of engagement with the consumer to amplify and augment the connection between alcohol and the sport spectator experience. The discussion highlights the powerful combination of sport and social media as a mechanism by which these brands seek to interact with consumers and encourage them to both create and promote content to their social networks. These strategies allow alcohol brands to extend their marketing efforts in a manner which can elude alcohol codes and prove difficult for regulators to identify and control. [Westberg K, Stavros C, Smith ACT, Munro G, Argus K. An examination of how alcohol brands use sport to engage consumers on social media. Drug Alcohol Rev 2018;37:28-35].

Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1).

Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.