Structure-property Relationships Reported for the New Drugs Approved in 2023.

Drug-like properties play pivotal roles in drug adsorption, distribution, metabolism, excretion, and toxicity. Therefore, efficiently optimizing these properties is essential for the successful development of novel therapeutics. Understanding the structure-property relationships of clinically approved drugs can provide valuable insights for drug design and optimization strategies. Among the new drugs approved in 2023, which include 31 small-molecule drugs in the US, the structure-property relationships of nine drugs were compiled from the medicinal chemistry literature, in which detailed information on pharmacokinetic and/or physicochemical properties was reported not only for the final drug but also for its key analogs generated during drug development. The structure-property relationships of nine newly approved drugs are summarized, including three kinase inhibitors and three G-protein-coupled receptor antagonists. Several optimization strategies, such as bioisosteric replacement and steric handle installation, have successfully produced clinical candidates with enhanced physicochemical and pharmacokinetic properties. The summarized structure-property relationships demonstrate how appropriate structural modifications can effectively improve overall drug-like properties. The ongoing exploration of structure- property relationships of clinically approved drugs is expected to offer valuable guidance for developing future drugs.

The Structure-property Relationships of Clinically Approved Protease Inhibitors.

BACKGROUND: Proteases play important roles in the regulation of many physiological processes, and protease inhibitors have become one of the important drug classes. Especially because the development of protease inhibitors often starts from a substrate- based peptidomimetic strategy, many of the initial lead compounds suffer from pharmacokinetic liabilities. OBJECTIVE: To reduce drug attrition rates, drug metabolism and pharmacokinetics studies are fully integrated into modern drug discovery research, and the structure-property relationship illustrates how the modification of the chemical structure influences the pharmacokinetic and toxicological properties of drug compounds. Understanding the structure- property relationships of clinically approved protease inhibitor drugs and their analogues could provide useful information on the lead-to-candidate optimization strategies. METHODS: About 70 inhibitors against human or pathogenic viral proteases have been approved until the end of 2021. In this review, 17 inhibitors are chosen for the structure- property relationship analysis because detailed pharmacological and/or physicochemical data have been disclosed in the medicinal chemistry literature for these inhibitors and their close analogues. RESULTS: The compiled data are analyzed primarily focusing on the pharmacokinetic or toxicological deficiencies found in lead compounds and the structural modification strategies used to generate candidate compounds. CONCLUSION: The structure-property relationships hereby summarized how the overall druglike properties could be successfully improved by modifying the structure of protease inhibitors. These specific examples are expected to serve as useful references and guidance for developing new protease inhibitor drugs in the future.

Structure-property Relationships Reported for the New Drugs Approved in 2022.

BACKGROUND: The structure-property relationship illustrates how modifying the chemical structure of a pharmaceutical compound influences its absorption, distribution, metabolism, excretion, and other related properties. Understanding structure-property relationships of clinically approved drugs could provide useful information for drug design and optimization strategies. METHOD: Among new drugs approved around the world in 2022, including 37 in the US, structure- property relationships of seven drugs were compiled from medicinal chemistry literature, in which detailed pharmacokinetic and/or physicochemical properties were disclosed not only for the final drug but also for its key analogues generated during drug development. RESULTS: The discovery campaigns for these seven drugs demonstrate extensive design and optimization efforts to identify suitable candidates for clinical development. Several strategies have been successfully employed, such as attaching a solubilizing group, bioisosteric replacement, and deuterium incorporation, resulting in new compounds with enhanced physicochemical and pharmacokinetic properties. CONCLUSION: The structure-property relationships hereby summarized illustrate how proper structural modifications could successfully improve the overall drug-like properties. The structure-property relationships of clinically approved drugs are expected to continue to provide valuable references and guides for the development of future drugs.

The Structure-property Relationships of GPCR-targeted Drugs Approved between 2011 and 2021.

BACKGROUND: G-protein-coupled receptors (GPCRs) are the largest family of membrane receptors and the most intensively studied drug targets. Given the physiological importance of signal transduction by GPCRs and the recent progress in the structure determination of membrane proteins, the development of GPCR antagonists and agonists is expected to continue to be a major area of medicinal chemistry research. METHODS: The structure-property relationship illustrates how the modification of the chemical structure influences the absorption, distribution, metabolism, excretion, and other related properties of drug compounds. Understanding the structure-property relationships of clinically approved GPCR-targeted drugs and their analogues could provide useful information on the lead-to-candidate optimization strategies. RESULTS: Among more than 50 GPCR antagonists and agonists approved in the last decade, the structure-property relationships of 17 drugs are compiled from medicinal chemistry literature, in which detailed pharmacokinetic and toxicological properties are disclosed not only for the final drug candidate but also for key analogues generated during the lead optimization campaign. CONCLUSION: The structure-property relationships hereby summarized demonstrate how in vitro and in vivo properties of the membrane protein-targeted ligands could be effectively optimized, in many cases, without requiring a significant change in the molecular size. This information is expected to provide valuable insights to expedite new GPCR-targeted drug development.

The Structure-property Relationships of Clinically Approved Protein Kinase Inhibitors.

BACKGROUND: Protein kinase inhibitors have become one of the most successful classes of small-molecule drugs during the last decades. In modern drug discovery, considering 'drug-like' physicochemical and pharmacokinetic properties as early as possible in drug design is widely acknowledged as an important strategy to reduce drug attrition rates. METHODS: In this review, clinically approved 25 protein kinase inhibitors and their key analogues reported in medicinal chemistry literature were compared for their biological, physicochemical, and pharmacokinetic properties. Although there is no common trajectory to follow through complex drug discovery campaigns, knowledge of the structure- activity relationship obtained from the successful lead optimization studies might be extended to other drug design efforts. RESULTS: Among more than 70 protein kinase inhibitors clinically approved around the world, the structure-activity relationships of 25 inhibitors and their key analogues are compiled from medicinal chemistry literature, in which detailed results from the 'lead-tocandidate' stage are available with associated property data. For the other inhibitors, such information has not been disclosed in the literature, or the available data is limited and not sufficient to provide clear structural analysis. CONCLUSION: The structure-property relationships summarized for 25 inhibitors and their analogues illustrate general guidelines for lead optimization and candidate selection, and this information could be extended for better property-based drug design in the future.

Midwavelength Infrared Colloidal Nanowire Laser.

Realizing bright colloidal infrared emitters in the midwavelength infrared (or mid-IR), which can be used for low-power IR light-emitting diodes (LEDs), sensors, and deep-tissue imaging, has been a challenge for the last few decades. Here, we present colloidal tellurium nanowires with strong emission intensity at room temperature and even lasing at 3.6 µm (ω) under cryotemperature. Furthermore, the second-harmonic field at 1.8 µm (2ω) and the third-harmonic field at 1.2 µm (3ω) are successfully generated thanks to the intrinsic property of the tellurium nanowire. These unique optical features have never been reported for colloidal tellurium nanocrystals. With the colloidal midwavelength infrared (MWIR) Te nanowire laser, we demonstrate its potential in biomedical applications. MWIR lasing has been clearly observed from nanowires embedded in a human neuroblastoma cell, which could further realize deep-tissue imaging and thermotherapy in the near future.

Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway.

Glutathione (GSH), the most abundant nonprotein thiol functioning as an antioxidant, plays critical roles in maintaining the core functions of mesenchymal stem cells (MSCs), which are used as a cellular immunotherapy for graft-versus-host disease (GVHD). However, the role of GSH dynamics in MSCs remains elusive. Genome-wide gene expression profiling and high-throughput live-cell imaging assays revealed that CREB1 enforced the GSH-recovering capacity (GRC) of MSCs through NRF2 by directly up-regulating NRF2 target genes responsible for GSH synthesis and redox cycling. MSCs with enhanced GSH levels and GRC mediated by CREB1-NRF2 have improved self-renewal, migratory, anti-inflammatory, and T cell suppression capacities. Administration of MSCs overexpressing CREB1-NRF2 target genes alleviated GVHD in a humanized mouse model, resulting in improved survival, decreased weight loss, and reduced histopathologic damages in GVHD target organs. Collectively, these findings demonstrate the molecular and functional importance of the CREB1-NRF2 pathway in maintaining MSC GSH dynamics, determining therapeutic outcomes for GVHD treatment.

Monitoring Glutathione Dynamics and Heterogeneity in Living Stem Cells.

Glutathione (GSH) is a major antioxidant in cells, and plays vital roles in the cellular defense against oxidants and in the regulation of redox signals. In a previous report, we demonstrated that stem cell function is critically affected by heterogeneity and dynamic changes in cellular GSH concentration. Here, we present a detailed protocol for the monitoring of GSH concentration in living stem cells using FreSHtracer, a real-time GSH probe. We describe the steps involved in monitoring GSH concentration in single living stem cells using confocal microscopy and flow cytometry. These methods are simple, rapid, and quantitative, and able to demonstrate intracellular GSH concentration changes in real time. We also describe the application of FreSHtracer to the sorting of stem cells according to their GSH content using flow cytometry. Typically, microscopic or flow cytometric analyses of FreSHtracer and MitoFreSHtracer signals in living stem cells take ~2~3 h, and the fractionation of stem cells into subpopulations on the basis of cellular GSH levels takes 3~4.5 h. This method could be applied to almost every kind of mammalian cell with minor modifications to the protocol described here.

Real-Time Monitoring of Glutathione in Living Cells Reveals that High Glutathione Levels Are Required to Maintain Stem Cell Function.

The core functions of stem cells (SCs) are critically regulated by their cellular redox status. Glutathione is the most abundant non-protein thiol functioning as an antioxidant and a redox regulator. However, an investigation into the relationship between glutathione-mediated redox capacity and SC activities is hindered by lack of probe. Here, we demonstrate that cyanoacrylamide-based coumarin derivatives are ratiometric probes suitable for the real-time monitoring of glutathione levels in living SCs. These probes revealed that glutathione levels are heterogeneous among subcellular organelles and among individual cells and show dynamic changes and heterogeneity in repopulating SCs depending on oxidative stress or culture conditions. Importantly, a subpopulation of SCs with high glutathione levels exhibited increased stemness and migration activities in vitro and showed improved therapeutic efficiency in treating asthma. Our results indicate that high glutathione levels are required for maintaining SC functions, and monitoring glutathione dynamics and heterogeneity can advance our understanding of the cellular responses to oxidative stress.

Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists.

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.

A bifunctional colorimetric fluorescent probe for Hg(2+) and Cu(2+) based on a carbazole-pyrimidine conjugate: chromogenic and fluorogenic recognition on TLC, silica-gel and filter paper.

A bifunctional fluorescent probe based on a carbazole-pyrimidine conjugate for Hg(2+) and Cu(2+) detection was designed and synthesized. Probe 3 exhibits red shifts in its absorption and fluorescence spectra with significant visual color changes in the presence of these ions. The detection limits of probe 3 for these metal ions were in the nanomolar range. The probe could also be useful as a solid optical sensor for Hg(2+) and Cu(2+).

Cystamine induces AIF-mediated apoptosis through glutathione depletion.

Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death.

Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.

This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules.

Crystal structure of transglutaminase 2 with GTP complex and amino acid sequence evidence of evolution of GTP binding site.

Transglutaminase2 (TG2) is a multi-functional protein involved in various cellular processes, including apoptosis, differentiation, wound healing, and angiogenesis. The malfunction of TG2 causes many human disease including inflammatory disease, celiac disease, neurodegenerative diseases, tissue fibrosis, and cancers. Protein cross-linking activity, which is representative of TG2, is activated by calcium ions and suppressed by GTP. Here, we elucidated the structure of TG2 in complex with its endogenous inhibitor, GTP. Our structure showed why GTP is the optimal nucleotide for interacting with and inhibiting TG2. In addition, sequence comparison provided information describing the evolutionary scenario of GTP usage for controlling the activity of TG2.

Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.

We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.

High-efficiency blue phosphorescent organic light-emitting diodes using a carbazole and carboline-based host material.

A novel bipolar host 9-(4-(9H-pyrido[2,3-b]indol-9-yl)phenyl)-9H-3,9'-bicarbazole (pBCb2Cz) was prepared for high efficiency blue phosphorescent organic light-emitting diodes (PhOLEDs), a high triplet energy (ET) material, employing electron-deficient α-carboline. pBCb2Cz (ET = 2.93 eV) was effective as a host material for FIrpic- and FCNIrpic-based blue PhOLEDs, and highest quantum efficiencies of 23.0 and 16.2%, respectively, were achieved.

A novel tellurophene-containing conjugated polymer with a dithiophenyl diketopyrrolopyrrole unit for use in organic thin film transistors.

A new tellurophene-based π-conjugated polymer, PDTDPPTe, was synthesized. PDTDPPTe exhibits a smaller optical band gap (E(g)(opt) = 1.25 eV) than thiophene-based PDTDPPT (E(g)(opt) = 1.30 eV). Thin-film transistors comprising PDTDPPTe displayed outstanding performance (µ(max) = 1.78 cm(2) V(-1) s(-1), I(on)/I(off) = 10(5-6)).

Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.

Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.

Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction.

Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.

Synthesis and biological evaluation of 2-(arylethynyl)quinoline derivatives as mGluR5 antagonists for the treatment of neuropathic pain.

We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.