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International audience; Mini-EUSO is a high-sensitivity imaging telescope that observes the Earth from the ISS in the near ultraviolet band (290÷ 430 nm), through the nadir-facing, UV-transparent window in the Russian Zvezda module. The instrument, launched in 2019, has a field of view of 44∘, a spatial resolution on the Earth’s surface of 6.3 km and a temporal sampling rate of 2.5 microseconds. Thanks to its triggering and on-board processing, the telescope is capable of detecting UV emissions of cosmic, atmospheric, and terrestrial origin on different time scales, from a few microseconds up to tens of milliseconds. The optics is composed of two Fresnel lenses focusing light onto an array of 36 Hamamatsu Multi-Anode PhotoMultiplier Tubes, for a total of 2304 pixels. The telescope also contains two cameras in the near-infrared and visible, an 8-by-8 array of Silicon-PhotoMultipliers and a series of UV sensors to manage night-day transitions. The scientific objectives range from the observation of atmospheric phenomena [lightning, Transient Luminous Events (TLEs), ELVES], the study of meteoroids, the search of interstellar meteoroids and strange quark matter, mapping of the Earth’s nocturnal emissions in the ultraviolet range, and the search of cosmic rays with energy above 1021 eV. The instrument has been integrated and qualified in 2019, with the final tests in Baikonur prior to its launch. Operations involve periodic installation in the Zvezda module of the station with observations during the crew night time, with periodic downlink of data samples, with the full data being sent to the ground via pouches containing the data disks. Mission planning involves the selection of the optimal orbits to maximize the scientific return of the instrument. In this work, we will describe the various phases of construction, testing, and qualification prior to the launch and the in-flight operations of the instrument on board the ISS.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

The growing interest in the use of luminescence thermometry for noncontact temperature reading under very specific conditions imposes the need to develop an approach allowing modification of the luminescence parameters of a thermometer accordingly to requirements. Therefore, in response to these expectations, this manuscript reports an approach to modulate the spectral position and luminescence thermal quenching rate of Fe3+ ions by modifying the crystal field strength and the host material composition of nanocrystalline AB2O4 type nanocrystals (A = Mg, Ca; B = Al, Ga). It was proved that in a group of MgAl2O4, MgGa2O4, CaAl2O4, and CaGa2O4 nanocrystals doped with Fe3+ ions, the emission spectral range, as well as the relative thermal sensitivity (from 0.2%/°C for MAO to 2.07%/°C for CGO) and the operating temperature range, can be easily modified by the host material composition. For instance, a maximal relative thermal sensitivity of 2.58%/°C is obtained for Fe3+, Tb3+ co-doped CaAl2O4 nanocrystals. The proposed approach is a step toward the intentional designing of a highly sensitive luminescence thermometer.

Despite the numerous advantages of lanthanide based luminescent thermometers, a major limitation is the limited brightness associated with the low absorption cross section of the 4f–4f transitions. In this paper, co-doping with Cr3+/4+ is proposed as a strategy to enhance the near-infrared luminescence emission of Nd3+/Er3+-based luminescent thermometers, as well as to modulate the temperature sensitivity of the ratio of Nd3+ to Er3+ in YAG microcrystals. It was found that an increase in the Cr3+ concentration leads to the enhancement of the YAG:Nd3+,Er3+ emission intensity via the Cr3+ → Ln3+ sensitization process. The quantitative analysis of the absolute brightness indicates the 30-fold enhancement of their near infrared emission upon broad white light excitation for 20% Cr3+ with respect to the non co-doped with the Cr3+ counterpart. In addition, the phonon-assisted nature of the simultaneously occurring Cr3+ → Ln3+ and Nd3+ → Cr4+ → Er3+ energy transfers leads to a 7-fold increase of the relative temperature sensitivity of the ratio of Nd3+ to Er3+ emission. In conclusion, co-doping with transition metals can enhance simultaneously the luminescence brightness and the temperature sensitivity of NIR luminescent thermometers, holding promise for sensitive and robust remote temperature sensing at physiological temperatures.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

Currently available temperature measurements or imaging at nano-micro scale are limited to fluorescent molecules and luminescent nanocrystals, whose spectral properties respond to temperature variation. The principle of operation of these conventional temperature probes is typically related to temperature induced multiphonon quenching or temperature dependent energy transfers, therefore, above 12%/K sensitivity and high thermal resolution remain a serious challenge. Here we demonstrate a novel class of highly sensitive thermographic phosphors operating in room temperature range with sub-kelvin thermal resolution, whose temperature readings are reproducible, luminescence is photostable and brightness is not compromised by thermal quenching. Corroborated with phase transition structural characterization and high spatio-temporal temperature imaging, we demonstrated that optically active europium ions are highly and smoothly susceptible to monoclinic to tetragonal phase transition in nanocrystalline (54 ± 14 nm) LiYO2 host, which is evidenced by changed number and the splitting of Stark components as well as by smooth variation of contribution between magnetic and electric dipole transitions. Further, reducing the size of phosphor from bulk to nanocrystalline matrix, shifted the phase transition temperature from 100 °C down to room temperature. These findings provide insights into the mechanism underlaying phase transition based luminescence nanothermometry and motivate future research toward new, highly sensitive, high temporal and spatial resolution nano-thermometers aiming at precise studying heat generation or diffusion in numerous biological and technology applications.

Herein, we show that the substitution of Sr2+ by trivalent lanthanide ions (Lu3+, La3+, Tb3+) in SrTiO3 nanocrystals stabilizes and enhances Ti3+ near-infrared emission (around 800 nm). This emission occurs from the 6-fold coordinated Ti3+ luminescent centers that appear in the vacancy–Ti3+–O form after lanthanide doping into the Sr2+ site. The strong dependence of the Ti3+ emission on temperature provided means for the tailored chemical engineering of luminescent nanonthermometers able to read the temperature in three ways: from the changes in Ti3+ emission intensity, excited-state lifetime, and from the ratio of Tb3+ and Ti3+ emission intensities. We demonstrated the unprecedented temperature sensitivity of the lifetime-based luminescent thermometer (8.83% K−1) with SrTiO3:Tb3+, along with exceptional repeatability in measurements.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)-H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)-H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C-H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

The principle of minimum Fisher information states that in the set of acceptable probability distributions characterizing the given system, it is best done by the one that minimizes the corresponding Fisher information. This principle can be applied to transaction processes, the dynamics of which can be interpreted as the market tendency to minimize the information revealed about itself. More information involves higher costs (information is physical). The starting point for our considerations is a description of the market derived from the assumption of minimum Fisher information for a strategy with a fixed financial risk. Strategies of this type that minimize Fisher information overlap with the well-known eigenstates of a the quantum harmonic oscillator. The analytical extension of this field of strategy to the complex vector space (traditional for quantum mechanics) suggests the study of the interference of the oscillator eigenstates in terms of their minimization of Fisher information. It is revealed that the minimum value of Fisher information of the superposition of the two strategies being the ground state and the second excited state of the oscillator, has Fisher information less than the ground state of the oscillator. Similarly, less information is obtained for the system of strategies (the oscillator eigenstates) randomized by the Gibbs distribution. We distinguish two different views on the description of Fisher information. One of them, the classical, is based on the value of Fisher information. The second, we call it transactional, expresses Fisher information from the perspective of the constant risk of market strategies. The orders of the market strategies derived from these two descriptions are different. From a market standpoint, minimizing Fisher information is equivalent to minimizing risk., Comment: 13 pages, 1 figure

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles., DNA-compatible C(sp3)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.

Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Backvall's ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation-π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.

Manuscript published in the Open Access Journal: Jovana Periša,Zoran Ristić, Wojciech Piotrowski, Željka Antić,Lukasz Marciniak and Miroslav D. Dramićanin All near-infrared multiparametric luminescence thermometry using Er3+, Yb3+-doped YAG nanoparticles RSC Adv., 2021, 11, 15933 doi:10.1039/d1ra01647d This paper presents four new temperature readout approaches to luminescence nanothermometry in spectral regions of biological transparency demonstrated onYb3+/Er3+-doped yttrium aluminum garnet nanoparticles.Under the 10638 cm-1excitation, down-shifting near infrared emissions (> 10000 cm-1) are identified as those originating from Yb3+ions’2F5/2➝2F7/2(~ 9709 cm-1) and Er3+ions’4I13/2➝4I15/2(~6494 cm-1) electronic transitions and used for 4 conceptually different luminescence thermometry. Observed variations in luminescence parameters with temperature offered an exceptional base for studying multiparametric temperature readouts.These include the temperature-dependence of: (i) intensity ratio between emissions from Stark components of Er3+4I13/2level;(ii) intensity ratio between emissions of Yb3+(2F5/2➝2F7/2transition) and Er3+(4I13/2➝4I15/2transition); (iii) band shift and bandwidth and (iv) lifetime of the Yb3+emission (2F5/2➝2F7/2transition) with maximal sensitivities of1 %K-1,0.8 %K-1,0.09 cm-1K-1, 0.46 %K-1and 0.86 %K-1,respectively. The multimodal temperature readout provided by this material enables its application in different luminescence thermometry setups as well as improved the reliability of the temperature sensing by the cross-validation between measurements.

The synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor 3 is described. This complex structure contains a tetrazole modified by a chiral hemiaminal carbonate prodrug. A reg...

The present authors have put forward a quantum game theory based model of market prices movements. By using Fisher information, we present a construction of an equation of Schrodinger type for probability distributions for relationship between demand and supply. Various analogies between quantum physics and market phenomena can be found.

The co-doping of SrTiO3:Mn4+ luminescent nanocrystals with trivalent lanthanide ions (Ln3+ = Lu3+, Tm3+, Er3+, Ho3+, Dy3+, Eu3+, and La3+) is demonstrated as a new strategy for significant sensitivity improvement of lifetime-based luminescent thermometers. SrTiO3:Mn4+:Ln3+ nanocrystals of about 25 nm diameter were prepared by the modified Pechini method and characterized using X-ray powder diffraction and electron microscopy techniques. The temperature dependence of Mn4+ emission in SrTiO3 was considerably altered by the co-doping of Ln3+ due to the cooperating effects of Mn4+ → Ti3+ and Mn4+ → Ln3+ energy transfers. A substantial enhancement of the relative sensitivity of lifetime-based thermometry as high as 145% with respect to the unco-doped nanocrystals reveals the success of the approach. The obtained values of maximal relative sensitivity for different Ln3+ co-dopants are 5.10% K−1 at 290 K for Er3+, 5.00% K−1 at 301 K for Eu3+, 4.84% K−1 at 303 K for Dy3+, 4.71% K−1 at 289 K for Ho3+, and 3.87% K−1 at 290.7 K for Lu3+.

The growing interest in the use of luminescence thermometry for noncontact temperature reading in very specific conditions imposes the need to develop an approach allowing modification of the luminescence parameters of the thermometer accordingly to the requirements. Therefore, in response to these expectations, this manuscript reports an approach to modulating the spectral position and the luminescence thermal quenching rate of Fe3+ ions by modifying the crystal field strength and the host material composition of nanocrystalline AB2O4 type nanocrystals (A= Mg, Ca; B=Al, Ga). It was proved that in a group of MgAl2O4, MgGa2O4, CaAl2O4, and CaGa2O4 nanocrystals doped with Fe3+ ions the emission spectral range, as well as the relative thermal sensitivity (from 0.2%/oC for MAO to 2.07%/oC for CGO) and the operating temperature range, can be easily modified by the host material composition. For instance, a maximal relative thermal sensitivity of 2.58%/oC is obtained for Fe3+, Tb3+ co-doped CaAl2O4 nanocrystals. The proposed approach is a step toward the intentional designing of the highly sensitive luminescent thermometer., Financial support from the NanoTBtech European Union's Horizon 2020 FET Open programme under grant agreement no. 801305

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health.One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis., info:eu-repo/semantics/published

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel-Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.

Preparative chemical reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Here we show that cobalt catalysts will react with the alkenes of unsaturated tertiary amines under dilute, aqueous, buffered conditions and promote efficient cycloisomerization, in many cases mediating a formal Friedel-Crafts reaction. We find the constraining conditions of biorthogonal chemistry to be beneficial for reaction efficiency as we obtain superior conversion at low catalyst concentration and maintain competent rates in dilute conditions. The efficiency at high dilution in the presence of buffer and nucleobases suggests that these conditions may find use on or in the presence of biomolecules.

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a single experiment. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produces billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of bifunctional building blocks, and facilitates access to certain setups for DELs. Furthermore, sequential C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA Encoded Libraries have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently Reversible Adsorption to Solid Support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C–S, C–P and N–S linkages into DELs, which are underrepresented in the canonical methods.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a single experiment. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produces billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of bifunctional building blocks, and facilitates access to certain setups for DELs. Furthermore, sequential C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

It is well known that light-induced multiple trans-cis-trans photoisomerizations of azobenzene derivatives attached to various matrices (polymeric, liquid crystalline polymers) result in polymer mass movement leading to generation of surface reliefs. The reliefs can be produced at small as well as at large light intensities. When linearly polarized light is used in the process, directional photo-induced molecular orientation of the azo molecules occurs, which leads to the generation of optical anisotropy in the system, providing that thermal effects are negligible. On the other hand, large reliefs are observed at relatively strong laser intensities when the optofluidization process is particularly effective. In this article, we describe the competitive thermocapillary Marangoni effect of polymer mass motion. We experimentally prove that the Marangoni effect occurs simultaneously with the optofluidization process. It destroys the orientation of the azopolymer molecules and results in cancelation of the photo-induced birefringence. Our experimental observations of polymer surface topography with atomic force microscopy are supported by suitable modelings.

Summary Objective This study aimed to explore the changes in vocal fold inferior surface hypertrophy (VFISH) on vocal fold vibration by aerodynamic and acoustic analysis. The present study allows us to gain new insights into the subglottal convergence angle (SCA), which will change with VFISH. Study Design The study is prospective, and designed for repeated measures with each excised canine larynx serving as own control. Subjects and Methods Three degrees of VFISH, initial, mild, and severe, were simulated by injecting different doses of fructose injections into the inferior surface of the vocal folds of 10 excised canine larynges. Computed tomographic images of the larynx were gathered, and three-dimensional models of the airway and vocal folds were reconstructed using the Mimics software. The SCA was measured from the reconstructed models. Phonation threshold flow (PTF), phonation threshold pressure (PTP), and mean flow rate (MFR) were recorded directly in the excised canine larynx phonation setup. Glottal resistance (GR), sound pressure level (SPL), fundamental frequency (F0), and formants 1–4 (F1–4) were measured when subglottal pressure (P sub ) was at 1.5 kPa or 2.5 kPa, separately. Using ordinary one-way analysis of variance, we compared the aerodynamic outcomes and voice quality among the three groups of hypertrophy. Results The SCA, PTP, and PTF increased with the degree of VFISH. When the P sub was controlled at 1.5 kPa or 2.5 kPa, F0 also increased significantly with the degree of VFISH of the excised canine larynges. The MFR, GR, SPL, and F1–4 had little change between the three groups and were not significantly different. Conclusion The VFISH makes onset phonation more difficult, increases the SCA, and increases the F0 in sustained phonation.

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.

A novel series of morpholine-based nonsteroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F-isotopologue validated our liver-targeting approach.