ACS Med Chem Lett
· 2026 May · PMID 42157822
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The Viewpoint addresses the importance of correct designations of stereochemistry in chiral drugs. Sources of confusion typically arise from merging disparate concepts such as handedness, configuration, and chiroptical p...The Viewpoint addresses the importance of correct designations of stereochemistry in chiral drugs. Sources of confusion typically arise from merging disparate concepts such as handedness, configuration, and chiroptical properties. This Viewpoint recommends the consistent use of configurational labeling, while avoiding ambiguous and context-dependent nomenclature.
Yu Z, Shi W, Qian Z
… +8 more, Mei X, Huang X, Chen X, Wang W, Zhang T, Chen X, Li Z, Zheng C
ACS Med Chem Lett
· 2026 May · PMID 42157821
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The clinical application of doxorubicin in cancer therapy is significantly limited by its severe cardiotoxicity, with complex mechanisms. No effective protective agents are currently available, creating an urgent clinica...The clinical application of doxorubicin in cancer therapy is significantly limited by its severe cardiotoxicity, with complex mechanisms. No effective protective agents are currently available, creating an urgent clinical need. In this study, through structural optimization of ebselen, we developed a series of isoselenazolinones with improved water solubility and glutathione peroxidase (GPx)-like activity. The most promising acidic and basic derivatives, and , exhibited a 7.0- and 10.4-fold increase in activity compared to the lead compound, alongside a 16- and 160-fold improvement in water solubility. Frontier molecular orbital theory calculation results showed a good correlation with the observed structure-activity relationships. Furthermore, compound significantly protected cardiomyocytes from doxorubicin-induced injury, preventing 75% of the loss in cell viability at 20 μM. Preliminary mechanistic studies suggested that this protection is mediated by inhibiting oxidative stress and ferroptosis. This study provides a promising class of active compounds for the treatment of doxorubicin-induced cardiotoxicity.
ACS Med Chem Lett
· 2026 May · PMID 42157820
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Provided herein are novel dihydroisoquinolinone-amide compounds as GIPR agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such comp...Provided herein are novel dihydroisoquinolinone-amide compounds as GIPR agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.
Feher M, Swett RJ, Walsh RT
… +2 more, Davis E, Williams CI
ACS Med Chem Lett
· 2026 May · PMID 42157819
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DNA-encoded library (DEL) screening enables identification of small-molecule binders from libraries containing billions of compounds, yet much of the resulting structure-activity relationship (SAR) information remains un...DNA-encoded library (DEL) screening enables identification of small-molecule binders from libraries containing billions of compounds, yet much of the resulting structure-activity relationship (SAR) information remains underutilized. Here, we describe DEL2PH4, an automated ligand-based workflow that converts DEL screening data into three-dimensional pharmacophore models by integrating statistically enriched compounds with structurally related unenriched analogs, which serve as negative examples during model construction. The resulting pharmacophores capture consensus interaction features across DEL families and enable the extraction of actionable 3D SAR information from primary DEL screening data, independent of resynthesis or activity measurements. Application to a MerTK kinase DEL screen demonstrates strong enrichment of positives over decoy molecules in retrospective benchmarking, recovery of known experimentally validated actives from external data sets, and consistency with experimentally determined X-ray binding modes. DEL2PH4 provides a general strategy for translating DEL screening outputs into interpretable 3D models that support virtual screening, scaffold hopping, and medicinal chemistry optimization.
ACS Med Chem Lett
· 2026 May · PMID 42157818
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The invention in this patent application relates to 4-oxo-4,5-dihydro-1-pyrazolo-[3,4-]-pyrimidine-3-carbonitrile derivatives represented herein by formula 1. These compounds are PDE9 inhibitors and may be useful as ther...The invention in this patent application relates to 4-oxo-4,5-dihydro-1-pyrazolo-[3,4-]-pyrimidine-3-carbonitrile derivatives represented herein by formula 1. These compounds are PDE9 inhibitors and may be useful as therapeutic agents for the treatment of cardiovascular and cerebrovascular diseases, such as hypertension, chronic kidney disease and heart failure, and neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.
ACS Med Chem Lett
· 2026 May · PMID 42157817
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Targeted protein degradation continues to reshape therapeutic strategy, yet the structural constraints of cereblon (CRBN) ligand chemistry limit broader application. Patent application WO 2026/043898 A1 discloses acyclic...Targeted protein degradation continues to reshape therapeutic strategy, yet the structural constraints of cereblon (CRBN) ligand chemistry limit broader application. Patent application WO 2026/043898 A1 discloses acyclic glutarimide-based precursors that undergo in situ cyclization to generate active degraders. This prodrug-like strategy enables temporally controlled CRBN engagement, enhances conjugation compatibility, and expands the degrader design space across oncology and related indications.
Leriche G, Barmare F, Toth JI
… +13 more, Jamborcic A, Kampert TL, Steadman K, Yang L, Fish S, Daniele E, McCarrick M, Kallel EA, Li X, Thompson PA, Parker GS, Freeman-Cook K, Bailey S
ACS Med Chem Lett
· 2026 May · PMID 42157816
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Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we re...Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we report the discovery of BRD4-selective monovalent direct degraders acting through DCAF11, identified by ultrahigh-throughput screening and subsequently optimized through a structure-guided medicinal chemistry campaign. Structure-activity relationship (SAR) studies support a direct degrader mechanism and culminated in the identification of the orally bioavailable compound . In vitro, induces rapid, complete, and selective degradation of BRD4 and exhibits potent antiproliferative activity in acute myeloid leukemia (AML) models. In vivo, treatment resulted in complete tumor regression in the AML MV-4-11 xenograft model. Collectively, this lays the groundwork for the rational development of monovalent direct degraders with applications extending beyond BRD4.
Paliwal A, Paliwal S, Sharma S
… +2 more, Mishra AK, Jain S
ACS Med Chem Lett
· 2026 May · PMID 42157815
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Diabetes is the most prevalent metabolic disorder distinguished by increased blood glucose levels. Unfortunately, none of the marketed treatments can cure the ailment. Glucokinase has recently emerged as a novel target a...Diabetes is the most prevalent metabolic disorder distinguished by increased blood glucose levels. Unfortunately, none of the marketed treatments can cure the ailment. Glucokinase has recently emerged as a novel target acting in both the liver and the pancreas. The activity of this novel protein in the liver is regulated by a protein called glucokinase regulatory protein (GKRP). The study aimed to identify novel GKRP modulators and evaluate their potential as antidiabetic agents using a comprehensive approach incorporating in silico, in vitro, and in vivo methods. In the quest for novel GKRP modulators, pharmacophore models were developed using Hypogen and HipHop methodologies. The optimal pharmacophore hypothesis, featuring 1HBA, 1HY, 1HBD, and 1RA, demonstrated a root mean-square deviation of 0.88 Å and a high correlation coefficient of 0.88. Fisher's randomization and Cat Scramble tests confirmed the statistical validity of the models, with a 95% confidence level. The validated pharmacophore model was employed in a virtual screening of the NCI database, resulting in the retrieval of key hits, including NCS 1972 and NCS 80683. These compounds were subjected to docking studies and in vitro enzyme-based GKRP modulatory assay, revealing favorable binding interactions with the GKRP active site and IC of 1.60 and 3.04 nM, respectively. In vivo evaluations showed that NCS 1972 (2.5 mg/kg) significantly improved lipid profiles, reduced liver hypertrophy and adiposity, and enhanced body mass index, 0.27 ± 0.02 g/mm, 0.21 ± 0.12g/mm, 0.70 ± 2.82 g/cm respectively, compared to the HFD-STZ group. Histopathological analyses demonstrated substantial cellular restoration in pancreatic and liver tissues, with NCS 1972 exhibiting superior efficacy over NCS 80683. Additionally, gene expression studies revealed that both compounds corrected HFD-STZ-induced dysregulation of glucose metabolism and inflammatory markers. These findings underscore the significant therapeutic potential of NCS 1972 in mitigating diabetes, suggesting its promise as a novel antidiabetic agent.
ACS Med Chem Lett
· 2026 May · PMID 42157814
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This highlight describes novel substituted 2-((tetrahydro-1H-pyrrolizin-7a-(5H)-yl)-methoxy)-pyrido-[4,3-]-pyrimidine derivatives as potential inhibitors for Kirsten Rat Sarcoma (KRAS) G12C, which is extensively expresse...This highlight describes novel substituted 2-((tetrahydro-1H-pyrrolizin-7a-(5H)-yl)-methoxy)-pyrido-[4,3-]-pyrimidine derivatives as potential inhibitors for Kirsten Rat Sarcoma (KRAS) G12C, which is extensively expressed across a variety of cancers. The patent provides detailed description of the preparation routes, methods of use, biological activity evaluations, and pharmaceutical compositions.
ACS Med Chem Lett
· 2026 May · PMID 42157813
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This highlight outlines the development of novel substituted 1-phenyl-2,3-dihydroquinazolin-4-(1H)-one derivatives as potential inhibitor candidates for Na 1.8 voltage-gated sodium channels (Na 1.8), which is upregulated...This highlight outlines the development of novel substituted 1-phenyl-2,3-dihydroquinazolin-4-(1H)-one derivatives as potential inhibitor candidates for Na 1.8 voltage-gated sodium channels (Na 1.8), which is upregulated or activated to transmit nociceptive signaling in a range of pain-related disorders. The invention includes details on preparation methods, biological activity assays, and pharmaceutical compositions.
ACS Med Chem Lett
· 2026 May · PMID 42157812
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Advances in computational design have greatly accelerated antimicrobial peptide engineering. In this study, three -derived peptides (PcDBS1R1, PcDBS1R5, and PcDBS1R9), generated using the Joker computational design algor...Advances in computational design have greatly accelerated antimicrobial peptide engineering. In this study, three -derived peptides (PcDBS1R1, PcDBS1R5, and PcDBS1R9), generated using the Joker computational design algorithm, were synthesized and characterized for their structural and functional properties. Biophysical analyses revealed that PcDBS1R5 and PcDBS1R9 predominantly adopted α-helical structures with high amphipathicity, whereas PcDBS1R1 exhibited greater structural plasticity. PcDBS1R5 and PcDBS1R9 displayed antibacterial activity against an clinical isolate, whereas PcDBS1R1 showed pronounced antibiofilm effects. None of the peptides exhibited cytotoxicity toward murine macrophages, and all significantly reduced nitric oxide production in lipopolysaccharide-stimulated macrophages, suggesting potential anti-inflammatory activity. Overall, these findings demonstrate that computer-aided design of -derived peptides can yield molecules with antibiofilm, and immunomodulatory properties, minimal cytotoxicity, and promising therapeutic potential as scaffolds for next-generation peptide-based treatments targeting biofilm-associated bacterial infections.
Bungard CJ, Breslin MJ, Boyce CW
… +17 more, Chobanian HR, Clements MK, Dalby SM, Ehrhart J, Huang C, Jones KG, Kraus RL, Layton ME, Li Y, Madeira M, Perkins JJ, Stachel SJ, Vardigan JD, Wang D, Zhou X, Santarelli VP, Burgey CS
ACS Med Chem Lett
· 2026 May · PMID 42157811
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Na1.8 is a key mediator of peripheral nociceptive signaling and an attractive nonopioid target for pain therapeutics. We report the discovery of , a potent, selective, and orally bioavailable Na1.8 inhibitor amenable to...Na1.8 is a key mediator of peripheral nociceptive signaling and an attractive nonopioid target for pain therapeutics. We report the discovery of , a potent, selective, and orally bioavailable Na1.8 inhibitor amenable to once-daily dosing. Optimization of an initial lead, guided by reduction of PXR activation, and dose optimization focusing on half-life and volume ligand efficiency are described. demonstrates a favorable pharmacokinetic profile in preclinical species, as well as efficacy in preclinical models for pain.
ACS Med Chem Lett
· 2026 May · PMID 42157810
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We report the total synthesis of sulfobacin A () and its stereoisomeric analogue via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without c...We report the total synthesis of sulfobacin A () and its stereoisomeric analogue via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of to 7.8%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.
Le Manach C, Viklund J, Kwapień K
… +1 more, Winiwarter S
ACS Med Chem Lett
· 2026 Apr · PMID 41982739
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Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity, the ability of a c...Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity, the ability of a compound to adapt its conformation to different environments (solvent or membrane), has been suggested as a key molecular property. Here, using a diverse set of PROTACs from our portfolio, we evaluate whether published guidelines including predicted or experimental chameleonicity descriptors could refine AstraZeneca's internal guidelines for designing orally absorbed PROTACs. We did not find such a trend. Instead, reducing the efflux ratio in Caco-2 cells emerged as a useful addition to our guidelines.
Khan I, Hettikankanamalage AA, Cui Y
… +1 more, Crich D
ACS Med Chem Lett
· 2026 Apr · PMID 41982738
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The attachment of solvent-exposed basic amines to kinase inhibitors via an aliphatic chain is a strategy commonly employed to increase aqueous solubility but one that is often complicated by increased human ether-a-go-go...The attachment of solvent-exposed basic amines to kinase inhibitors via an aliphatic chain is a strategy commonly employed to increase aqueous solubility but one that is often complicated by increased human ether-a-go-go (hERG) activity and reduced metabolic stability. Extrapolating from previous work on the replacement of the solubilizing morphilinoalkyl and -methyl piperazinoalkyl chains in the tyrosine kinase inhibitors gefitinib and bosutinib by isosteric hydroxylamines with concomitant reduction in hERG activity without loss of potency against the target kinases, using the PAK1 kinase inhibitor FRAX1036 as model, we describe our exploration of endo- and exocyclic hydroxylamine units as replacements of solubilizing -methyl-4-piperidinylalkyl chains. These studies culminate with the development of the 5-methyl-1,2,5-oxadiazepan-5-yl moiety as an isosteric replacement of the parent -methyl-4-piperidinylalkyl group without loss of potency as a PAK1 inhibitor, a 2-fold increase in selectivity over hERG inhibition, parent-like rates of metabolism by human liver microsomes and MDCKII and Caco-2 efflux ratios.
ACS Med Chem Lett
· 2026 Apr · PMID 41982737
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The vasopressin V receptor (VR) is a class A G protein-coupled receptor (GPCR) that plays a pivotal role in the regulation of renal water homeostasis and has been implicated in the pathogenesis of autosomal dominant poly...The vasopressin V receptor (VR) is a class A G protein-coupled receptor (GPCR) that plays a pivotal role in the regulation of renal water homeostasis and has been implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) through sustained activation of cyclic adenosine monophosphate (cAMP) signaling. Pharmacological antagonism of VR has emerged as a clinically validated strategy for attenuating cyst growth. However, the therapeutic application of currently available VR antagonists remains constrained by safety liability and a relatively narrow chemical space. A recent study employed systematic structure-activity relationship (SAR) analyses to expand existing design paradigms for VR antagonists, leading to the identification and synthesis of a series of structurally diverse VR antagonist analogues. Supported by multidimensional pharmacological evaluations, these findings provide an important framework for the rational design and optimization of next-generation therapeutics for ADPKD.
ACS Med Chem Lett
· 2026 Apr · PMID 41982736
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Provided herein are novel indazole compounds as PKMYT1 kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.Provided herein are novel indazole compounds as PKMYT1 kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
Cuřínová P, Jöe M, Cesar F
… +11 more, Nicol A, Schwan K, Kohout M, Varrichio C, Saleh A, Wheelock CE, Jóhannesson G, Eigner V, Tribble JR, Brancale A, Williams PA
ACS Med Chem Lett
· 2026 Apr · PMID 41982735
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We designed and synthesized a series of novel 1,2,3,4-tetrahydroquinoxaline derivatives and evaluated their ability to increase nicotinamide adenine dinucleotide (NAD) levels in primary cortical neurons. Several compound...We designed and synthesized a series of novel 1,2,3,4-tetrahydroquinoxaline derivatives and evaluated their ability to increase nicotinamide adenine dinucleotide (NAD) levels in primary cortical neurons. Several compounds demonstrated nanomolar potency and enabled the establishment of clear structure-activity relationships (SAR), highlighting key substituents required for activity. Qualitative 3DSAR analysis further identified favorable steric, electrostatic, and hydrophobic features associated with NAD enhancement. Selected lead compounds were assessed for drug metabolism and pharmacokinetics (DMPK) properties, showing good cell permeability and species-dependent metabolic stability in liver microsomes, with improved stability in human systems compared with rodent systems. These findings identify tetrahydroquinoxalines as a promising class of neuronal NAD-boosting agents and provide a strong foundation for further optimization toward neuroprotective drug candidates.
van der Straat R, Oerlemans R, Cong Y
… +10 more, Boxma J, Bulai RG, Río-Bergé C, Koekemoer L, Zarganes Tzitzikas T, Guan Z, Marples PG, Reggiori F, Groves M, Dömling A
ACS Med Chem Lett
· 2026 Apr · PMID 41982734
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The SARS-CoV-2 main protease (3CLpro) is a well-validated target for structure-guided inhibitor discovery. Here, we report α-aminomethyl tetrazole inhibitors accessed via the Ugi tetrazole multicomponent reaction (UT-4CR...The SARS-CoV-2 main protease (3CLpro) is a well-validated target for structure-guided inhibitor discovery. Here, we report α-aminomethyl tetrazole inhibitors accessed via the Ugi tetrazole multicomponent reaction (UT-4CR), enabling rapid exploration of non-classical chemical space. Initial design and modeling suggested a binding mode analogous to Ugi-derived (U-4CR) 3CLpro inhibitors, with heteroaromatic substituents engaging the S1 pocket. However, crystallographic analysis revealed an unexpected binding orientation in which the tetrazole core itself occupies the S1 pocket and forms the key interaction with His163, while the modeled substituents are solvent-exposed. This revised binding mode rationalizes the observed structure-activity relationships. Installation of an electrophilic warhead yielded covalent inhibitors with sub-micromolar enzymatic potency, and lead compound displayed modest antiviral activity in infected cells. These results highlight UT-4CR-derived tetrazoles as a platform for probing the 3CLpro binding space and underscore the importance of early crystallographic validation.
ACS Med Chem Lett
· 2026 Apr · PMID 41982733
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Provided herein are novel compounds as glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating diabetes, and processes for preparing such compounds.Provided herein are novel compounds as glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating diabetes, and processes for preparing such compounds.