Structural studies identify angiotensin II receptor blocker-like compounds as branched-chain ketoacid dehydrogenase kinase inhibitors.

The mammalian mitochondrial branched-chain ketoacid dehydrogenase (BCKD) complex is a multienzyme complex involved in the catabolism of branched-chain amino acids. BCKD is regulated by the BCKD kinase, or BCKDK, which binds to the E2 subunit of BCKD, phosphorylates its E1 subunit, and inhibits enzymatic activity. Inhibition of the BCKD complex results in increased levels of branched-chain amino acids and branched-chain ketoacids, and this buildup has been associated with heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. To find BCKDK inhibitors for potential treatment of these diseases, we performed both NMR and virtual fragment screening and identified tetrazole-bearing fragments that bind BCKDK at multiple sites. Through structure-based virtual screening expanding from these fragments, the angiotensin receptor blocker class antihypertension drugs and angiotensin receptor blocker-like compounds were discovered to be potent BCKDK inhibitors, suggesting potential new avenues for heart failure treatment combining BCKDK inhibition and antihypertension.

Cracked Film Lithography with CuGaOx Buffers for Bifacial CdTe Photovoltaics.

Bifacial CdTe solar cells with greater power density than the monofacial baselines are demonstrated by using a CuGaOx rear interface buffer that passivates while reducing sheet resistance and contact resistance. Inserting CuGaOx between the CdTe and Au increases mean power density from 18.0 ± 0.5 to 19.8 ± 0.4 mW cm-2 for one sun front illumination. However, coupling CuGaOx with a transparent conductive oxide leads to an electrical barrier. Instead, CuGaOx is integrated with cracked film lithography (CFL)-patterned metal grids. CFL grid wires are spaced narrowly enough (≈10 µm) to alleviate semiconductor resistance while retaining enough passivation and transmittance for a bifacial power gain: bifacial CuGaOx /CFL grids generate 19.1 ± 0.6 mW cm-2 for 1 sun front + 0.08 sun rear illumination and 20.0 ± 0.6 mW cm-2 at 1 sun front + 0.52 sun rear-the highest reported power density at field albedo conditions for a scaled polycrystalline absorber.

Fundamentals of Using Cracked Film Lithography to Pattern Transparent Conductive Metal Grids for Photovoltaics.

The fundamentals of using cracked film lithography (CFL) to fabricate metal grids for transparent contacts in solar cells were studied. The underlying physics of drying-induced cracks were well-predicted by an empirical correlation relating crack spacing to capillary pressure. CFL is primarily controlled by varying the crack template thickness, which establishes a three-way tradeoff between the areal density of cracks, crack width, and spacing between cracks, which in turn determine final grid transmittance, grid sheet resistance, and the semiconductor resistance for a given solar cell. Since CFL uses a lift-off process, an additional constraint is that the metal thickness must be less than 1/3 of the crack template thickness. The transmittance/grid sheet resistance/wire spacing tradeoffs measured in this work were used to calculate solar cell performance: CFL-patterned grids should outperform screen-printed grids for narrow cells (0.5-2 cm wide) and/or cells with high semiconductor sheet resistance (≥100 Ω/sq), making CFL attractive for monolithically integrated thin-film photovoltaic modules.

5-Aryltetrazoles from Direct C-H Arylation with Aryl Bromides.

A mild, direct C-H arylation of 1-substituted tetrazoles to 5-aryltetrazoles is developed using a Pd/Cu cocatalytic system with readily available aryl bromides. The methodology avoids late-stage usage of azides and tolerates a wide range of functionalities.

Floating Photovoltaic Systems: Assessing the Technical Potential of Photovoltaic Systems on Man-Made Water Bodies in the Continental United States.

Floating photovoltaic (FPV) systems, also called floatovoltaics, are a rapidly growing emerging technology application in which solar photovoltaic (PV) systems are sited directly on water. The water-based configuration of FPV systems can be mutually beneficial: Along with providing such benefits as reduced evaporation and algae growth, it can lower PV operating temperatures and potentially reduce the costs of solar energy generation. Although there is growing interest in FPV, to date there has been no systematic assessment of technical potential in the continental United States. We provide the first national-level estimate of FPV technical potential using a combination of filtered, large-scale datasets, site-specific PV generation models, and geospatial analytical tools. We quantify FPV co-benefits and siting considerations, such as land conservation, coincidence with high electricity prices, and evaporation rates. Our results demonstrate the potential of FPV to contribute significantly to the U.S. electric sector, even using conservative assumptions. A total of 24 419 man-made water bodies, representing 27% of the number and 12% of the area of man-made water bodies in the contiguous United States, were identified as being suitable for FPV generation. FPV systems covering just 27% of the identified suitable water bodies could produce almost 10% of current national generation. Many of these eligible bodies of water are in water-stressed areas with high land acquisition costs and high electricity prices, suggesting multiple benefits of FPV technologies.

High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates.

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α-alkyl,ß-aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates. Cyclobutanones with two stereogenic centers are obtained in good to high yield, with high enantioselectivity and diastereoselectivity. Vital to this advance are the development of a novel approach to α,ß unsymmetrically disubstituted cyclobutenone substrates and the use of a high-throughput chiral ligand screening platform. The synthetic utility of both the boronic ester and ketone functionalities is displayed, with remarkable chemoselectivity for either group being possible in this small ring scaffold.

Tandem Solar Cells from Solution-Processed CdTe and PbS Quantum Dots Using a ZnTe-ZnO Tunnel Junction.

We developed a monolithic CdTe-PbS tandem solar cell architecture in which both the CdTe and PbS absorber layers are solution-processed from nanocrystal inks. Due to their tunable nature, PbS quantum dots (QDs), with a controllable band gap between 0.4 and ∼1.6 eV, are a promising candidate for a bottom absorber layer in tandem photovoltaics. In the detailed balance limit, the ideal configuration of a CdTe (Eg = 1.5 eV)-PbS tandem structure assumes infinite thickness of the absorber layers and requires the PbS band gap to be 0.75 eV to theoretically achieve a power conversion efficiency (PCE) of 45%. However, modeling shows that by allowing the thickness of the CdTe layer to vary, a tandem with efficiency over 40% is achievable using bottom cell band gaps ranging from 0.68 and 1.16 eV. In a first step toward developing this technology, we explore CdTe-PbS tandem devices by developing a ZnTe-ZnO tunnel junction, which appropriately combines the two subcells in series. We examine the basic characteristics of the solar cells as a function of layer thickness and bottom-cell band gap and demonstrate open-circuit voltages in excess of 1.1 V with matched short circuit current density of 10 mA/cm2 in prototype devices.

Utilizing on- and off-line monitoring tools to follow a kinetic resolution step during flow synthesis.

In situ reaction monitoring tools offer the ability to track the progress of a synthetic reaction in real time to facilitate reaction optimization and provide kinetic/mechanistic insight. Herein, we report the utilization of flow NMR, flow IR, and other off-line spectroscopy tools to monitor the progress of a flow chemistry reaction. The on-line and off-line tools were selected to facilitate the stereoselective kinetic resolution of a key racemic monomer, which lacked a chromophore, making conventional reaction monitoring difficult. Copyright © 2016 John Wiley & Sons, Ltd.

Discovery of a novel Kv7 channel opener as a treatment for epilepsy.

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

Investigation of Sub-Bandgap Emission and Unexpected n-Type Behavior in Undoped Polycrystalline CdSexTe1-x.

Se alloying has enabled significantly higher carrier lifetimes and photocurrents in CdTe solar cells, but these benefits can be highly dependent on CdSexTe1-x processing. This work evaluates the optoelectronic, chemical, and electronic properties of thick (3 µm) undoped CdSexTe1-x of uniform composition and varied processing conditions (CdSexTe1-x evaporation rate, CdCl2 anneal, Se content) chosen to reflect various standard device processing conditions. Sub-bandgap defect emission is observed, which increased as Se content increased and with "GrV-optimized CdCl2" (i.e., CdCl2 anneal conditions used for group-V-doped devices). Low carrier lifetime is found for GrV-optimized CdCl2, slow CdSexTe1-x deposition, and low-Se films. Interestingly, all films (including CdTe control) exhibited n-type behavior, where electron density increased with Se up to an estimated ≈1017 cm-3. This behavior appears to originate during the CdCl2 anneal, possibly from Se diffusion leading to anion vacancy (e.g., VSe, VTe) and ClTe generation.

Hierarchical Transparent Back Contacts for Bifacial CdTe PV.

A hierarchical transparent back contact leveraging an AlGaOx passivating layer, Ti3C2Tx MXene with a high work function, and a transparent cracked film lithography (CFL) templated nanogrid is demonstrated on copper-free cadmium telluride (CdTe) devices. AlGaOx improves device open-circuit voltage but reduces the fill factor when using a CFL-templated metal contact. Including a Ti3C2Tx interlayer improves the fill factor, lowers detrimental Schottky barriers, and enables metallization with CFL by providing transverse conduction into the nanogrid. The bifacial performance of an AlGaOx/Ti3C2Tx/CFL gold contact is evaluated, reaching 19.5% frontside efficiency and 2.8% backside efficiency under 1-sun illumination for a copper-free, group-V doped CdTe device. Under dual illumination, device power generation reached 200 W/m2 with 0.1 sun backside illumination.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

Dependence of the minority-carrier lifetime on the stoichiometry of CdTe using time-resolved photoluminescence and first-principles calculations.

CdTe is one of the most promising materials for thin-film solar cells. However, further improvement of its performance is hindered by its relatively short minority-carrier lifetime. Combining theoretical calculations and experimental measurements, we find that for both intrinsic CdTe and CdTe solar cell devices, longer minority-carrier lifetimes can be achieved under Cd-rich conditions, in contrast to the previous belief that Te-rich conditions are more beneficial. First-principles calculations suggest that the dominant recombination centers limiting the minority-carrier lifetime are the Te antisite and Te interstitial. Therefore, we propose that to optimize the solar cell performance, extrinsic p-type doping (e.g., N, P, or As substitution on Te sites) in CdTe under Cd-rich conditions should be a good approach to simultaneously increase both the minority-carrier lifetime and hole concentration.

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.

Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.

Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.

Building perovskite solar cells that last.

An inorganic halide perovskite solar cell architecture promises multiyear stability.

Identifying optimal photovoltaic technologies for underwater applications.

Improving solar energy collection in aquatic environments would allow for superior environmental monitoring and remote sensing, but the identification of optimal photovoltaic technologies for such applications is challenging as evaluation requires either field deployment or access to large water tanks. Here, we present a simple bench-top characterization technique that does not require direct access to water and therefore circumvents the need for field testing during initial trials of development. Employing LEDs to simulate underwater solar spectra at various depths, we compare Si and CdTe solar cells, two commercially available technologies, with GaInP cells, a technology with a wide bandgap close to ideal for underwater solar harvesting. We use this method to show that while Si cells outperform both CdTe and GaInP cells under terrestrial AM1.5G solar irradiance, CdTe and GaInP cells outperform Si cells at depths >2 m, with GaInP cells operating with underwater efficiencies approaching 54%.

Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide.

Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4'-alkyl and 4'-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.

Surface Modification of Backsheets Using Coupling Agents for Roll-To-Roll Processed Thin-Film Solar Photovoltaic (PV) Module Packaging Application.

For many flexible electronic and photonic devices, moisture stability is one of the most important factors that affects its short- and long-term performance. To maintain the performance, the device should be packaged in such a way that it hermetically blocks moisture from the device; however, in practice, it is rather difficult to achieve. The more practical solution is to impede the moisture ingress to the device. In optoelectronic devices that will be outdoors like solar cells, the interfacial adhesion strength between the encapsulant layer (adhesive) and a moisture barrier layer is also a critical parameter. This paper presents surface modifications of poly(ethylene terephthalate) (PET) carrier films, one of the layers in the trilayer barrier film that directly adheres to an encapsulant, using chemical, UV/ozone, and both treatments to improve adhesion with the thermoset encapsulant polymer material. Whereas previous studies also utilized treatment methods to increase the wettability characteristics, in this paper, we not only present the results of the adhesion strength upon various techniques to achieve good adhesion but also screen their behavior upon exposure to a damp-heat (60 °C, 90% RH) environment. We found that the combined treatment method increases the adhesion by up to 12.1-fold and demonstrates up to a 200% increase in adhesion strength even upon our severe damp-heat environmental condition.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.