3,355 results match your criteria ACS Medicinal Chemistry Letters[Journal]


Novel Quinoline Compounds as EZH2 Inhibitors for Treating Cancer.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 13;13(5):755-756. Epub 2022 Apr 13.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

5-HT Receptor Modulators for Therapeutic Use in the Treatment of Obsessive-Compulsive Disorder and Other Psychological Disorders.

Authors:
Robert B Kargbo

ACS Med Chem Lett 2022 May 20;13(5):770-772. Epub 2022 Apr 20.

Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

Identification of 2-Pyridinylindole-Based Dual Antagonists of Toll-like Receptors 7 and 8 (TLR7/8).

ACS Med Chem Lett 2022 May 25;13(5):812-818. Epub 2022 Apr 25.

Bristol Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.

The toll-like receptors (TLRs) play key roles in activation of the innate immune system. Aberrant activation of TLR7 and TLR8 pathways can occur in the context of autoimmune disorders due to the elevated presence and recognition of self-RNA as activating ligands. Control of this unintended activation via inhibition of TLR7/8 signaling holds promise for the treatment of diseases such as psoriasis, arthritis, and lupus. Read More

View Article and Full-Text PDF

Indazole and Benzoisoxazole Compounds as Dihydroorotate Dehydrogenase Inhibitors for Treating Acute Myelogenous Leukemia.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 22;13(5):763-764. Epub 2022 Apr 22.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Fluorescence Studies: A9 Peptide, Functionalized with a Fluorogenic Probe, Interacts with Its Receptor Model HER2-DIVMP.

ACS Med Chem Lett 2022 May 11;13(5):807-811. Epub 2022 Apr 11.

Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy.

A recently developed synthetic protocol allowed for the functionalization of the active peptide A9 with a fluorogenic probe, which is useful for studying biomolecular interactions. Essentially, a nucleophilic attack on a halo-substituted benzofurazan is selectively performed by a cysteine sulfhydryl group. The process is assisted by the basic catalysis of activated zeolites (4 Å molecular sieves) and promoted by microwave irradiation. Read More

View Article and Full-Text PDF

Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides.

ACS Med Chem Lett 2022 May 14;13(5):833-840. Epub 2022 Apr 14.

Discovery Chemistry, Janssen Research & Development L.L.C., San Diego, California 92121, United States.

Acrylamides are privileged electrophiles used in targeted covalent therapies, often installed at the end of a synthetic sequence due to their reactive nature. Herein, we report several diene-acrylamide adducts with a range of thermal stabilities toward retro-Diels-Alder deprotection of the acrylamide, enabling this masked functionality to be introduced early in a synthetic route and deprotected in a specific temperature range. Through kinetic studies, we identify solvent and structural trends that impact the stability of trimethylsilyl cyclopentadiene (TMS-CP) acrylamide adducts. Read More

View Article and Full-Text PDF

Synthesis and Evaluation of Small Molecule Disruptors of the Aha1/Hsp90 Complex for the Reduction of Tau Aggregation.

ACS Med Chem Lett 2022 May 15;13(5):827-832. Epub 2022 Apr 15.

Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, 310 McCourtney Hall, Notre Dame, Indiana 46556, United States.

KU-177 was recently shown to disrupt interactions between Hsp90 and Aha1 . Subsequent studies in recombinant thioflavin T (ThT) assays demonstrated that KU-177 ablates Aha1-driven enhancement of Hsp90-dependent tau aggregation, which was confirmed by TEM. Using KU-177 as a lead compound, derivatives of KU-177 were synthesized and evaluated for their ability to disrupt Aha1/Hsp90 interactions and inhibit P301L tau aggregation. Read More

View Article and Full-Text PDF

New ZW4864 Derivatives as Small-Molecule Inhibitors for the β-Catenin/BCL9 Protein-Protein Interaction.

ACS Med Chem Lett 2022 May 25;13(5):865-870. Epub 2022 Apr 25.

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.

A series of 1-(3-(2-amino-2-oxoethoxy)phenyl)piperidine-3-carboxamide derivatives was reported as new small-molecule β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) inhibitors. Compounds - were discovered to inhibit the β-catenin/BCL9 PPI with = 0.85-2. Read More

View Article and Full-Text PDF

Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating Copper(II).

ACS Med Chem Lett 2022 May 21;13(5):792-798. Epub 2022 Apr 21.

Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, 2231 6th Street SE, 2-147 CCRB, Minneapolis, Minnesota 55455, United States.

Ten eleven translocation (TET) dioxygenases 1-3 are non-heme Fe(II) and α-ketoglutarate dependent enzymes that catalyze oxidation of 5-methylcytosine (5mC) in DNA to hydroxymethyl-C, formyl-C, and carboxy-C. This typically leads to gene activation and epigenetic remodeling. Most known inhibitors of TET are α-ketoglutarate mimics that may interfere with other α-ketoglutarate dependent enzymes. Read More

View Article and Full-Text PDF

5-Oxopyrrolidine-3-carboxamides as Na1.8 Inhibitors for Treating Pain Disorders, Cough Disorders, and Acute and Chronic Itch Disorders.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 14;13(5):761-762. Epub 2022 Apr 14.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Novel Cyclic Cyanoenone Derivatives as KEAP1Modulators for Treating Neurodegenerative Diseases.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 19;13(5):777-778. Epub 2022 Apr 19.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

KRAS Inhibitors and Target Engagement Technology: From Undruggable to Druggable Targets in Cancer Therapeutics.

Authors:
Robert B Kargbo

ACS Med Chem Lett 2022 May 6;13(5):752-754. Epub 2022 Apr 6.

Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

2-Aminoquinazolines as LRRK2 Inhibitors for Treating Parkinson's Disease.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 22;13(5):775-776. Epub 2022 Apr 22.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Novel BTK Inhibitors for Treating Autoimmune Disorders and Cancer.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 14;13(5):759-760. Epub 2022 Apr 14.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Substituted -Heteroaryl--Pyridinylacetamides as P2X4 Modulators for Treating Pain.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 19;13(5):765-766. Epub 2022 Apr 19.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Novel CFTR Modulators for Treating Cystic Fibrosis.

Authors:
Ram W Sabnis

ACS Med Chem Lett 2022 May 11;13(5):757-758. Epub 2022 Apr 11.

Smith, Gambrell & Russell LLP, 1105 West Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States.

View Article and Full-Text PDF

Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.

ACS Med Chem Lett 2022 May 29;13(5):848-854. Epub 2022 Apr 29.

Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is ; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Read More

View Article and Full-Text PDF

Long-Awaited Small-Molecule Drug Candidate for Drugging the Next Undruggable KRAS Mutant in Cancer Therapy.

Authors:
Robert B Kargbo

ACS Med Chem Lett 2022 May 20;13(5):773-774. Epub 2022 Apr 20.

Usona Institute, 277 Granada Drive, , San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

3-Pyrrolidine-indole Derivatives as 5-HT2-Selective Receptor Modulators for the Potential Treatment of Mental Disorders.

Authors:
Robert B Kargbo

ACS Med Chem Lett 2022 May 26;13(5):749-751. Epub 2022 Apr 26.

Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

The -Trisubstituted Hydroxylamine Isostere and Its Influence on Lipophilicity and Related Parameters.

ACS Med Chem Lett 2022 May 20;13(5):799-806. Epub 2022 Apr 20.

Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.

The influence of substitution of an -trisubstituted hydroxylamine (-NR-OR'-) unit for a hydrocarbon (-CHR-CH-), ether (-CHR-OR'-), or amine (-NR-CHR'-) moiety on lipophilicity and other ADME parameters is described. A matched molecular pair analysis was conducted across five series of compounds, which showed that the replacement of carbon-carbon bonds by -trisubstituted hydroxylamines typically leads to a reduction in log comparable to that achieved with a tertiary amine group. In contrast, the weakly basic -trisubstituted hydroxylamines have greater log values than tertiary amines. Read More

View Article and Full-Text PDF

Synthesis and Antitumor Activity of Diosgenin Hydroxamic Acid and Quaternary Phosphonium Salt Derivatives.

ACS Med Chem Lett 2022 May 19;13(5):786-791. Epub 2022 Apr 19.

Key Laboratory of General Chemistry of the National Ethnic Affairs Commission, School of Chemistry and Environment, Southwest Minzu University, Chengdu 610041, China.

Diosgenin, a component separated from Dioscorea plants, is an important starting material for steroid hormone drugs and semisynthetic steroids. In the work, two series of diosgenin derivatives were designed, synthesized, and evaluated for their cellular anticancer activities. Most of the target compounds exhibited good inhibitory activities against four cell lines, Aspc-1 (human colon adenocarcinoma cells), H358 (human nonsmall cell lung cancer cells), HCT116 (human colorectal adenocarcinoma cells), and SW620 (human metastatic pancreatic cancer cells). Read More

View Article and Full-Text PDF

Synthesis and Biological Characterization of a Series of 2-Sulfonamidebenzamides as Allosteric Modulators of MrgX1.

ACS Med Chem Lett 2022 May 19;13(5):841-847. Epub 2022 Apr 19.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States.

The present study describes our continued efforts in the discovery and characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1. MrgX1 has been shown to be an attractive target as a nonopioid receptor for the potential treatment of chronic pain. Working from our original compound, ML382, and utilizing iterative medicinal chemistry, we have identified key halogen substituents that improve MrgX1 potency by ∼8-fold. Read More

View Article and Full-Text PDF

Small-Molecule Inhibitor of the Oncogenic KRAS Mutant for the Treatment of Currently Incurable Cancer.

Authors:
Robert B Kargbo

ACS Med Chem Lett 2022 May 20;13(5):767-769. Epub 2022 Apr 20.

Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity.

ACS Med Chem Lett 2022 May 16;13(5):779-785. Epub 2022 Mar 16.

Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.

Histone deacetylases (HDACs) 1-3 regulate chromatin structure and gene expression. These three enzymes are targets for cancer chemotherapy and have been studied for the treatment of immune disorders and neurodegeneration, but there is a lack of selective pharmacological tool compounds to unravel their individual roles. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, which causes a delay in inhibitor-enzyme equilibration and may affect assay readout. Read More

View Article and Full-Text PDF

Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies.

ACS Med Chem Lett 2022 May 21;13(5):819-826. Epub 2022 Apr 21.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

The Janus kinase 2 (JAK2) pseudokinase domain (JH2) is an ATP-binding domain that regulates the activity of the catalytic tyrosine kinase domain (JH1). Dysregulation of JAK2 JH1 signaling caused by the V617F mutation in JH2 is implicated in various myeloproliferative neoplasms. To explore if JAK2 activity can be modulated by a small molecule binding to the ATP site in JH2, we have developed several ligand series aimed at selectively targeting the JAK2 JH2 domain. Read More

View Article and Full-Text PDF

Discovery of 2-Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity.

ACS Med Chem Lett 2022 May 3;13(5):855-864. Epub 2022 May 3.

Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.

A selection of compounds from a proprietary library, based on chemical diversity and various biological activities, was evaluated as potential inhibitors of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a phenotypic-based screening assay. A compound based on a 2-phenylquinoline scaffold emerged as the most promising hit, with EC and CC values of 6 and 18 μM, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low μM activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 μM. Read More

View Article and Full-Text PDF

Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones.

ACS Med Chem Lett 2022 Apr 14;13(4):546-553. Epub 2022 Mar 14.

Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Venezuelan and eastern equine encephalitis viruses are disease-causing, neuropathic pathogens with no approved treatment options in humans. While expanding the pharmacophoric model of antialphaviral amidines prepared via a quinazolinone rearrangement, we discovered that diamine-treated, 2-dihalomethylquinolinones unexpectedly afforded ring-expanded piperazine-fused benzodiazepinones. Notably, this new chemotype (19 examples) showed potent, submicromolar inhibition of virus-induced cell death, >7-log reduction of viral yield, and tractable structure-activity relationships across both viruses. Read More

View Article and Full-Text PDF

Design, Synthesis, and Evaluation of PD-1/PD-L1 Antagonists Bearing a Benzamide Scaffold.

ACS Med Chem Lett 2022 Apr 29;13(4):586-592. Epub 2022 Mar 29.

State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry and Department of Biomedical Engineering, China Pharmaceutical University, Nanjing 210009, China.

Several antibodies targeting programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) have been approved by the U.S. Food and Drug Administration (FDA) for cancer therapy. Read More

View Article and Full-Text PDF

[F]BIBD-181: A Novel Positron Emission Tomography Tracer Specific for Synaptic Vesicle Glycoprotein 2A.

ACS Med Chem Lett 2022 Apr 30;13(4):720-726. Epub 2022 Mar 30.

Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China.

Dysfunction or decreased expression of synaptic vesicle glycoprotein 2A (SV2A) is closely related to the progression of neurodegenerative diseases and psychiatric disorders. The development of positron emission tomography (PET) tracers targeting SV2A can provide a strong imaging basis for the diagnosis and treatment of these diseases. Herein we report the synthesis of the novel radiotracer [F]BIBD-181 and its preclinical evaluation. Read More

View Article and Full-Text PDF

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability.

ACS Med Chem Lett 2022 Apr 16;13(4):707-713. Epub 2022 Mar 16.

Department of Medicinal Chemistry and Molecular Pharmacology and Department of Chemistry, Purdue University, West Lafayette, Indiana 47906, United States.

Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation, which can generate bioinactive or toxic metabolites. Such is the case for dextromethorphan, which readily undergoes P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan, an -methyl-d-aspartate (NMDA) receptor antagonist that causes hallucinations and encourages recreational abuse. As a general strategy to minimize this undesired degradation, both deuteration and fluorination strategies might be exploited, though such strategies have rarely been compared in matched series. Read More

View Article and Full-Text PDF