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.

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.

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.

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.

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.

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.

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK).

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.

Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

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 Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK).

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy.

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

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.

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.

Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.