29,241 results match your criteria Journal of Medicinal Chemistry[Journal]


Fuplatin: an Efficient and Low-toxic Dual-prodrug.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin and 5-fluorouracil are widely used in clinic, but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU, were designed and synthesized. The assembled compounds 10-17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower toward the human normal lung cells than free drugs or their combinations. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00128
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http://dx.doi.org/10.1021/acs.jmedchem.9b00128DOI Listing
April 2019
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Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Department of Biochemistry and Biophysics , Texas A&M University , College Station , Texas 77843 , United States.

Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00020DOI Listing

Discovery of Pyrrolo[3,2-d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell Active Inhibitors of P300/CBP-Associated Factor Bromodomain.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Herein we report the discovery of a series of new PCAF bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship (SAR) analyses towards a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in HTRF assay and a KD of 78 nM in ITC assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00096DOI Listing

Novel deazaflavin analogues potently inhibited tyrosyl DNA phosphodiesterase 2 (TDP2) and strongly sensitized cancer cells toward treatment with topoisomerase II (TOP2) poison etoposide.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2 thus represents an attractive mechanism-based chemosensitization approach. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00274DOI Listing

Novel tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-Aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonist. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00241DOI Listing

Design and optimization leading to an orally active TTK protein kinase inhibitor with robust single agent efficacy.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of a potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. PK properties and kinome selectivity were optimized resulting in the identification of a new series of potent, selective and orally bioavailable TTK inhibitors. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01869DOI Listing
April 2019
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Discovery of 3-(indol-5-yl)-indazole derivatives as novel myeloid differentiation protein 2/toll-like receptor 4 antagonists for treatment of acute lung injury.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Acute lung injury (ALI) is often caused by systemic inflammatory responses. Targeting myeloid differentiation protein 2/toll-like receptor 4 (MD2-TLR4) complex may be a promising way to treat Gram-negative bacterial-induced inflammatory disorders. In this study, we report the design and synthesis of a new series of 3-(indol-5-yl)-indazoles, which were evaluated for their anti-inflammatory activities in macrophages. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00316DOI Listing

Structural basis for E. coli Penicillin Binding Protein (PBP) 2 inhibition, a platform for drug design.

J Med Chem 2019 Apr 17. Epub 2019 Apr 17.

Penicillin-binding proteins (PBPs) are the targets of the β-lactams, the most successful class of antibiotics ever developed against bacterial infections. Unfortunately, the worldwide and rapid spread of large spectrum β-lactam resistance genes such as carbapenemases is detrimental to the use of antibiotics in this class. New potent PBP inhibitors are needed, especially compounds that resist β-lactamase hydrolysis. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00338DOI Listing

Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway.

J Med Chem 2019 Apr 17. Epub 2019 Apr 17.

Complement Factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis type II (MPGNII) and paroxysmal nocturnal hemoglobinuria (PNH). Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00271DOI Listing

Drug Metabolism and Toxicology Special Issue Call for Papers.

J Med Chem 2019 Feb 11;62(3):1077. Epub 2019 Jan 11.

Vanderbilt University School of Medicine.

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00005
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http://dx.doi.org/10.1021/acs.jmedchem.9b00005DOI Listing
February 2019
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Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER).

J Med Chem 2019 Feb 18;62(3):1420-1442. Epub 2019 Jan 18.

The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERα degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 (32). Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01572DOI Listing
February 2019

Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

J Med Chem 2019 Apr 15. Epub 2019 Apr 15.

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01818
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http://dx.doi.org/10.1021/acs.jmedchem.8b01818DOI Listing
April 2019
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Novel Lysine-Based Thioureas as Mechanism-Based Inhibitors of Sirtuin 2 (SIRT2) with Anticancer Activity in a Colorectal Cancer Murine Model.

J Med Chem 2019 Apr 15. Epub 2019 Apr 15.

Sirtuin 2 (SIRT2) is a protein lysine deacylase that has been indicated as a therapeutic target for cancer. To further establish the role of SIRT2 in cancers, it is necessary to develop selective and potent inhibitors. Here, we report the facile synthesis of novel lysine-derived thioureas as mechanism-based SIRT2 inhibitors with anticancer activity. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00191DOI Listing

Inhibiting Hedgehog - An update on pharmacological compounds and targeting strategies.

J Med Chem 2019 Apr 15. Epub 2019 Apr 15.

Important steps in embryonic development are governed by the Hedgehog (Hh) signaling pathway, an evolutionary conserved signal transduction cascade. However, Hh activity is not only crucial during embryo formation, but is also involved in adult tissue repair and in several malignancies. Particularly due to its link to cancer, small molecule Hh pathway inhibitors have been developed and the first compounds have been approved for use in Hh-driven basal cell carcinoma. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00188DOI Listing

A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction.

J Med Chem 2019 Apr 12. Epub 2019 Apr 12.

The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule, p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00058DOI Listing
April 2019
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Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation.

J Med Chem 2019 Apr 12. Epub 2019 Apr 12.

Drug Discovery and Biomedical Sciences , College of Pharmacy , Columbia , South Carolina 29208 , United States.

Despite the clinical success of BRAF inhibitors like vemurafenib in treating metastatic melanoma, resistance has emerged through "paradoxical MEK/ERK signaling" where transactivation of one protomer occurs as a result of drug inhibition of the other partner in the activated dimer. The importance of the dimerization interface in the signaling potential of wild-type BRAF in cells expressing oncogenic Ras has recently been demonstrated and proposed as a site of therapeutic intervention in targeting cancers resistant to adenosine triphosphate competitive drugs. The proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signaling in malignant melanoma cells occurring through this drug target. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01288DOI Listing

Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

UNC Catalyst for Rare Diseases , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00350
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http://dx.doi.org/10.1021/acs.jmedchem.9b00350DOI Listing
April 2019
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Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-associated protein 1 : Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction.

J Med Chem 2019 Apr 11. Epub 2019 Apr 11.

The KEAP1/NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signalling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant drug-like inhibitor might be challenging. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00279DOI Listing

Identification of 5-substituted 2-acylaminothiazoles that activate Tat mediated transcription in HIV-1 latency models.

J Med Chem 2019 Apr 11. Epub 2019 Apr 11.

The persistent reservoir of cells latently infected with Human Immunodeficiency Virus (HIV) integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency reversing agents, however these drugs have undesirable toxicity and lack specificity for HIV. We utilised a novel HEK293 derived FlpIn dual-reporter cell line, that quantifies specific HIV provirus reactivation (LTR promoter) relative to non-specific host cell gene expression (CMV promoter), to identify the 5-substituted-2-acylaminothiazole hit class. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00462DOI Listing
April 2019
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Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants.

J Med Chem 2019 Apr 10. Epub 2019 Apr 10.

Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35, Keyan Road , Zhunan Town , Miaoli County 350 , Taiwan R.O.C.

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01845DOI Listing
April 2019
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Design and identification of a novel, functionally subtype selective GABA positive allosteric modulator (PF-06372865).

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

The design, optimization and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries which had the greatest odds of delivering the target profile. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00322DOI Listing
April 2019
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Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Department of Pharmaceutical Sciences , University of Kentucky , Lexington , Kentucky 40536 , United States.

Over the past 15 years, proteasome inhibitors (PIs), namely bortezomib, carfilzomib (Cfz) and ixazomib, have significantly improved the overall survival and quality-of-life for multiple myeloma (MM) patients. However, a significant portion of MM patients do not respond to PI therapies. Drug resistance is present either de novo or acquired after prolonged therapy through mechanisms that remain poorly defined. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01943DOI Listing
April 2019
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Galloyl Carbohydrates with Antiangiogenic Activity Mediated by Capillary Morphogenesis Gene 2 (CMG2) Protein Binding.

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

Vascular Biology Program , Boston Children's Hospital and Harvard Medical School , Boston , Massachusetts 02115 , United States.

We previously showed that a small molecule of natural origin, 1,2,3,4,6-penta- O-galloyl-β-d-glucopyranose (PGG), binds to capillary morphogenesis gene 2 (CMG2) with a submicromolar IC and also has antiangiogenic activity in vitro and in vivo. In this work, we synthetized derivatives of PGG with different sugar cores and phenolic substituents and tested these as angiogenesis inhibitors. In a high-throughput Förster resonant energy transfer-based binding assay, we found that one of our synthetic analogues (1,2,3,4,6-penta- O-galloyl-β-d-mannopyranose (PGM)), with mannose as central core and galloyl substituents, exhibit higher (up to 10×) affinity for CMG2 than the natural glucose prototype PGG and proved to be a potent angiogenesis inhibitor. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01988DOI Listing
April 2019
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D Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.

Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G-biased and β-arrestin2-biased D receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G pathway over β-arrestin2. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00508DOI Listing
April 2019
5.447 Impact Factor

Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Department of Chemical Biology 2, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 7 , 9747 AG Groningen , The Netherlands.

Various mechanisms for regulated cell death include the formation of oxidative mediators such as lipid peroxides and nitric oxide (NO). In this respect, 15-lipoxygenase-1 (15-LOX-1) is a key enzyme that catalyzes the formation of lipid peroxides. The actions of these peroxides are interconnected with nuclear factor-κB signaling and NO production. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00212DOI Listing
April 2019
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Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer (CRPC).

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

We report the design, optimization and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against other NRs subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain (LBD) provided solid structural basis for its antagonistic mechanism. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00327DOI Listing
April 2019
2 Reads

Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE Series EP Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE Analog (KMN-159) as a Potent EP Agonist.

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

A series of small molecule full agonists of the prostaglandin E type 4 (EP) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity against other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's five-fold increase in potency versus KMN-80. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00336
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http://dx.doi.org/10.1021/acs.jmedchem.9b00336DOI Listing
April 2019
3 Reads

Discovery of [1,2,4]Triazolo[4,3- a]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) , Ministry of Education , 103 Wenhua Road , Shenyang 110016 , PR China.

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction using small-molecule inhibitors is an emerging immunotherapeutic approach. A novel series of [1,2,4]triazolo[4,3- a]pyridines were designed and found to be potent inhibitors of the PD-1/PD-L1 interaction. Among them, compound A22 exhibited the most potent activity, as assessed by homogenous time-resolved fluorescence assay, with an IC of 92. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00312DOI Listing
April 2019
1 Read
5.447 Impact Factor

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01936DOI Listing
April 2019
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Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues.

J Med Chem 2019 Apr 9. Epub 2019 Apr 9.

Malaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the Plasmodium genus. Only a few WHO-recommended treatments are available to prevent or cure plasmodial infections, but genetic mutations in the causal parasites have led to onset of resistance against all commercial antimalarial drugs. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00182DOI Listing
April 2019
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Targeting the Thioredoxin System as a Strategy for Cancer Therapy.

J Med Chem 2019 Apr 16. Epub 2019 Apr 16.

Institute of Chinese Medicine, School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing 210023 , P. R. China.

Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate molecule, thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiological processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01595
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http://dx.doi.org/10.1021/acs.jmedchem.8b01595DOI Listing
April 2019
2 Reads

Rational Design of Short Peptide Variants by Using Kunitzin-RE, an Amphibian-Derived Bioactivity Peptide, for Acquired Potent Broad-Spectrum Antimicrobial and Improved Therapeutic Potential of Commensalism Coinfection of Pathogens.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Institute of Animal Nutrition , Northeast Agricultural University , Harbin 150030 , P. R. China.

Commensalism coinfection of pathogens has seriously jeopardized human health. Currently, Kunitzin-RE, as an amphibian-derived bioactivity peptide, is regarded as a potential antimicrobial candidate. However, its antimicrobial properties were unsatisfactory. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00149
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http://dx.doi.org/10.1021/acs.jmedchem.9b00149DOI Listing
April 2019
3 Reads

5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Department of Pharmacology and Toxicology , Michigan State University , East Lansing , Michigan 48824 , United States.

Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01772DOI Listing

Synthesis and Anti-HCV Activities of 4'-Fluoro-2'-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4'-Fluoro-2'- C-methyluridine 5'-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection.

J Med Chem 2019 Apr 19. Epub 2019 Apr 19.

Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States.

We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC values as low as 20 nM. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00143DOI Listing
April 2019
3 Reads
5.447 Impact Factor

Recent Progress in Natural-Product-Inspired Programs Aimed To Address Antibiotic Resistance and Tolerance.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy , University of Florida , Gainesville , Florida 32610 , United States.

Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00370DOI Listing
April 2019
1 Read

Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Na1.7 Inhibitors for the Treatment of Chronic Pain.

J Med Chem 2019 Apr 16. Epub 2019 Apr 16.

Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Na1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00141DOI Listing
April 2019
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Review of Transient Receptor Potential Canonical (TRPC5) Channel Modulators and Diseases.

J Med Chem 2019 Apr 17. Epub 2019 Apr 17.

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

Transient receptor potential canonical (TRPC) channels are highly homologous, nonselective cation channels that form many homo- and heterotetrameric channels. These channels are highly abundant in the brain and kidney and have been implicated in numerous diseases, such as depression, addiction, and chronic kidney disease, among others. Historically, there have been very few selective modulators of the TRPC family in order to fully understand their role in disease despite their physiological significance. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01954DOI Listing
April 2019
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3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models.

J Med Chem 2019 Apr 17. Epub 2019 Apr 17.

Laboratory of Growth Regulators , Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences , Šlechtitelů 27 , 783 71 Olomouc , Czech Republic.

Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2) H-pyrazolo[4,3- d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00189DOI Listing
April 2019
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Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.

J Med Chem 2019 Apr 18. Epub 2019 Apr 18.

Department of Drug Science and Technology , University of Turin , via P.Giuria 9 , 10125 Turin , Italy.

We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for the crystal structures in complex with the AMPA receptor GluA2 agonist-binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01986DOI Listing

Identification of Three-Way DNA Junction Ligands through Screening of Chemical Libraries and Validation by Complementary in Vitro Assays.

J Med Chem 2019 Apr 17. Epub 2019 Apr 17.

Institut de Chimie Moléculaire (ICMUB), CNRS UMR6302, UBFC , 21078 Dijon , France.

The human genome is replete with repetitive DNA sequences that can fold into thermodynamically stable secondary structures such as hairpins and quadruplexes. Cellular enzymes exist to cope with these structures whose stable accumulation would result in DNA damage through interference with DNA transactions such as transcription and replication. Therefore, the chemical stabilization of secondary DNA structures offers an attractive way to foster DNA transaction-associated damages to trigger cell death in proliferating cancer cells. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01978DOI Listing
April 2019
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Discovery and Structure-Based Optimization of Next Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors.

J Med Chem 2019 Apr 2. Epub 2019 Apr 2.

Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth suggesting that small molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00041DOI Listing

Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety.

J Med Chem 2019 Apr 12. Epub 2019 Apr 12.

Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Corrensstraße 48 , D-48149 Münster , Germany.

σ and/or σ receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ receptor affinity and σ:σ selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00449DOI Listing
April 2019
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Fifty Years in Search of Selective Antiviral Drugs.

Authors:
Erik De Clercq

J Med Chem 2019 Apr 12. Epub 2019 Apr 12.

Department of Microbiology and Immunology, Rega Institute for Medical Research , KU Leuven , Herestraat 49 , 3000 Leuven , Belgium.

Fifty years of research (1968-2018) toward the identification of selective antiviral drugs have been primarily focused on antiviral compounds active against DNA viruses (HSV, VZV, CMV, HBV) and retroviruses (HIV). For the treatment of HSV infections the aminoacyl esters of acyclovir were designed, and valacyclovir became the successor of acyclovir in the treatment of HSV and VZV infections. BVDU (brivudin) still stands out as the most potent among the marketed compounds for the treatment of VZV infections (i. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00175DOI Listing
April 2019
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Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

J Med Chem 2019 Apr 15. Epub 2019 Apr 15.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00223DOI Listing
April 2019
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Synthetic Approaches to the New Drugs Approved During 2017.

J Med Chem 2019 Apr 15. Epub 2019 Apr 15.

Groton Laboratories , Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 31 new chemical entities approved for the first time globally in 2017. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00196DOI Listing
April 2019
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Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors.

J Med Chem 2019 Apr 12. Epub 2019 Apr 12.

College of Life Sciences , Hebei Normal University , Shijiazhuang , Hebei 050024 , P. R. China.

Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00091DOI Listing
April 2019
5 Reads
5.447 Impact Factor