29,110 results match your criteria Journal of Medicinal Chemistry[Journal]


DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the last decade, the interference with bacterial Quorum Sensing (QS) (i.e. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00025DOI Listing
February 2019

Identification and Preclinical Pharmacology of ((1R,3S)-1-amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-Phosphate (S1P1) Receptor Modulator Advanced into Clinical Trials.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (FTY720, 1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in pre-clinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life (T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01695DOI Listing
February 2019

Cofactor Analogues as Active Site Probes in Lysine Acetyltransferases.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Lysine acetyltransferases (KATs, also termed histone acetyltransferases, HATs) catalyze the acetylation of substrate lysine residues by employing the cofactor acetyl-coenzyme A (AcCoA), thereby providing a dynamic control mechanism of protein function. Because of their major involvement in cell development and homeostasis, small molecule modulators of KAT activity are urgently needed to assess their therapeutic potential and for probing their underlying biology. Recent advances in the field suggest that targeting the cofactor binding site represents a promising strategy for identifying potent and selective ligands. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01887DOI Listing
February 2019

Structure-based In Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Potent Ebolavirus (EBOV) inhibitors will help to curtail outbreaks such as that which occurred in 2014-16 in West Africa. EBOV has on its surface a single glycoprotein (GP) critical for viral entry and membrane fusion. Recent high resolution complexes of EBOV GP with a variety of approved drugs revealed that binding to a common cavity prevented fusion of the virus and endosomal membranes, inhibiting virus infection. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01328DOI Listing
February 2019

Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1α kinase-endoribonuclease.

J Med Chem 2019 Feb 19. Epub 2019 Feb 19.

A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors was discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01721DOI Listing
February 2019

A Cinchona Alkaloid Antibiotic that Appears to Target ATP Synthase in Streptococcus pneumoniae.

J Med Chem 2019 Feb 19. Epub 2019 Feb 19.

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity towards Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01353DOI Listing
February 2019

Identification and Characterization of AES-135, a Hydroxamic Acid-based HDAC Inhibitor that Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer.

J Med Chem 2019 Feb 18. Epub 2019 Feb 18.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% one-year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01957DOI Listing
February 2019

Epidermal Growth Factor Receptor Targeted Multifunctional Photosensitizers for Bladder Cancer Imaging and Photodynamic Therapy.

J Med Chem 2019 Feb 18. Epub 2019 Feb 18.

The in vitro and in vivo anti-cancer activity of iodinated photosensitizers (PS) with and without erlotinib moiety was investigated in UMUC-3 [epidermal growth factor (EGFR) positive], T24 (EGFR low) cell lines, and tumored mice. Both the erlotinib conjugated PS 3 and 5 showed EGFR target specificity, but the position-3 erlotinib-PS conjugate 3 demonstrated lower photodynamic therapy (PDT) efficacy than the corresponding non-erlotinib analog 1, whereas the conjugate 5 containing an erlotinib moiety at position-17 of the PS gave higher tumor-uptake and long-term tumor cure (SCID mice bearing UMUC-3 tumors). PS-erlotinib conjugates in the absence of light were ineffective in vitro and in vivo, but robust apoptotic and necrotic cell death was observed in bladder cancer cells after exposing them with a laser light at 665 nm. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01927DOI Listing
February 2019

Design and Synthesis of 1,2-Bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine Hybrids as Potent Anticancer Agents that Inhibit Angiogenesis and Induce DNA Interstrand Crosslinks.

J Med Chem 2019 Feb 18. Epub 2019 Feb 18.

Hybrid molecules are composed of two pharmacophores with different biological activities. Here, we conjugated phthalazine moieties (anti-angiogenetic pharmacophore) and bis(hydroxymethyl)pyrrole moieties (DNA crosslinking agent) to form a series of bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine hybrids. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, arresting cell cycle progression at the G2/M phase, triggering apoptosis and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01689DOI Listing
February 2019
5.447 Impact Factor

Discovery of the Second Generation RORγ Inhibitors Composed of an Azole Scaffold.

J Med Chem 2019 Feb 18. Epub 2019 Feb 18.

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01567DOI Listing
February 2019

Remarkable brain penetration of cyclopentadienyl M(CO) (M = Tc, Re) derivatives of benzothiazole and benzimidazole paves the way for their application as diagnostic, with Single Photon Emission Computed Tomography (SPECT), and therapeutic agents for Alzheimer's disease.

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

The synthesis and evaluation of three novel Tc complexes (Tc-1 - Tc-3), and their corresponding Re complexes (Re-1 - Re-3) in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [CpTc(CO)] core, is reported. Both Tc and Re complexes were prepared from the corresponding ferrocenyl derivatives and the Re complexes were fully characterized by elemental analysis, spectroscopic methods and X-ray crystallography. The complexes exhibit effective in vitro binding to β-amyloid (Aβ) plaques and fibrils, inhibit Aβ fibril formation, significantly reduce Aβ-induced cytotoxicity and ROS production in neuronal cell cultures. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01949DOI Listing
February 2019

Targeting the MKK7-JNK (Mitogen-Activated Protein Kinase Kinase 7-c Jun N-Terminal Kinase) Pathway with Covalent Inhibitors.

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffold. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00102DOI Listing
February 2019

SGC-GAK-1: a chemical probe for cyclin G associated kinase (GAK).

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally-related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 inhibitor lacking GAK activity. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01213DOI Listing
February 2019

Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model.

J Med Chem 2019 Feb 14. Epub 2019 Feb 14.

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01847DOI Listing
February 2019

Design of N-Benzoxaborole Benzofuran GSK8175 - Optimization of Human PK Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

J Med Chem 2019 Feb 14. Epub 2019 Feb 14.

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which a N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein we describe second generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01719DOI Listing
February 2019
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Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites.

J Med Chem 2019 Feb 14. Epub 2019 Feb 14.

Gabazine, a GABAA receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance GHB. We herein report a study on the structural determinants of gabazine for binding to i) the orthosteric binding site of the GABAA receptor and ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogs with relatively high affinity (Ki 0. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00131DOI Listing
February 2019

Design, Synthesis, and Biological Evaluation of Novel Allosteric Protein Disulfide Isomerase Inhibitors.

J Med Chem 2019 Feb 13. Epub 2019 Feb 13.

Protein disulfide isomerase (PDI) is responsible for nascent protein folding in the endoplasmic reticulum (ER) and is critical for glioblastoma survival. To improve the potency of lead PDI inhibitor BAP2 ((E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzonitrile), we designed and synthesized 67 novel analogues. We determined that PDI inhibition relied on the A ring hydroxyl group of the chalcone scaffold and cLogP increase in the sulfonamide chain improved potency. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01951DOI Listing
February 2019

Discovery of a novel chemotype of histone lysine methyltransferase EHMT1/2 (GLP/G9a) inhibitors: rational design, synthesis, biological evaluation and co-crystal structure.

J Med Chem 2019 Feb 12. Epub 2019 Feb 12.

Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of non-quinazoline inhibitors of H3K9-specific methyltransferases G9a and GLP have been reported. Herein we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the under-investigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3H-benzo[e][1,4]diazepine scaffold. Our research efforts yielded the identification of compound 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNMT1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both PAMPA and PAMPA-BBB assays and, therefore, might potentially be a better candidate for animal studies. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b02008DOI Listing
February 2019
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Discovery of Carboline Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcal Meningitis.

J Med Chem 2019 Feb 12. Epub 2019 Feb 12.

Clinical treatment of cryptococcal meningitis (CM) remains a significant challenge due to the lack of effective and safe drug therapies. Developing novel CM therapeutic agents with novel chemical scaffolds and new modes of action is of great importance. Herein, new β-hexahydrocarboline derivatives were shown to possess potent anticryptococcal activities. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01598DOI Listing
February 2019
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Design, synthesis, and evaluation of (4R)-1-{3-[2-(F)fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one ([F]T-401) as a novel positron-emission tomography imaging agent for monoacylglycerol lipase.

J Med Chem 2019 Feb 12. Epub 2019 Feb 12.

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase involved in endocannabinoid and inflammatory signaling. Positron-emission tomography (PET) imaging of MAGL serves to validate target engagement of therapeutic MAGL inhibitors as well as to investigate MAGL levels under normal and disease conditions. However, PET radioligands with reversible binding kinetics for MAGL, which allow quantitative assessment of MAGL, are hitherto unavailable. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01576
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http://dx.doi.org/10.1021/acs.jmedchem.8b01576DOI Listing
February 2019
1 Read

Design, synthesis, and biological evaluation of itaconic acid derivatives as potential anti-influenza agents.

J Med Chem 2019 Feb 12. Epub 2019 Feb 12.

Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which renders antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20,000 compounds by performing a cell-based screening assay as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01683
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http://dx.doi.org/10.1021/acs.jmedchem.8b01683DOI Listing
February 2019
2 Reads

Antimicrobial peptides with high proteolytic resistance for combating gram-negative bacteria.

J Med Chem 2019 Feb 11. Epub 2019 Feb 11.

Poor proteolytic resistance is an urgent problem to be solved in the clinical application of AMPs, yet common solutions, such as complicated chemical modifications and utilization of D-amino acids, greatly increase the difficulty and cost of producing AMPs. In this work, a set of novel peptides was synthesized base on an anti-trypsin/chymotrypsin hydrolytic peptide structure unit (XYPX)n (X represents I, L and V; Y represents R and K), which was designed using a systematic natural amino acid arrangement. Of these peptides, 16 with 7 repeat units had the highest average selectivity index (GMSI=99. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01348DOI Listing
February 2019
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Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity towards Resistance-conferring Mutations.

J Med Chem 2019 Feb 11. Epub 2019 Feb 11.

The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually the discovery of new irreversible kinase inhibitors occurs serendipitously showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of the FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia (AML). Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01714DOI Listing
February 2019
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Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a µM MC4R Partial Agonist.

J Med Chem 2019 Feb 11. Epub 2019 Feb 11.

The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are established targets to treat diseases of positive and negative energy homeostasis. We previously reported (J. Med. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00053DOI Listing
February 2019

Highly Selective PTK2 Proteolysis Targeting Chimeras (PROTACs) to Probe Focal Adhesion Kinase Scaffolding Functions.

J Med Chem 2019 Feb 9. Epub 2019 Feb 9.

The focal adhesion tyrosine kinase (PTK2) is often over-expressed in human hepatocellular carcinoma (HCC) and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here we present two highly selective and functional PTK2 PROTACs utilizing VHL and cereblon ligands to hijack E3 ligases for PTK2 degradation. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01826
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http://dx.doi.org/10.1021/acs.jmedchem.8b01826DOI Listing
February 2019
1 Read

The medical uses of silver: history, myths and scientific evidence.

J Med Chem 2019 Feb 8. Epub 2019 Feb 8.

Silver has no biological role and it is particularly toxic to lower organisms. Although several silver formulations employed in medicine in the past century are prescribed and sold to treat certain medical conditions, most of the compounds, including those showing outstanding properties as antimicrobial or anticancer agents, are still in early stages of assessment, that is, in vitro studies, and may not make it to clinical trials. Unlike other heavy metals, there is no evidence that silver is a cumulative poison, but its levels can build up in the body tissues after prolonged exposure leading to undesired effects. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01439DOI Listing
February 2019

Discovery of an SSTR2-targeting maytansinoid conjugate (PEN-221) with potent activity in vitro and in vivo.

J Med Chem 2019 Feb 8. Epub 2019 Feb 8.

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2 targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3-octreotate. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b02036DOI Listing
February 2019

Improved RE31 analogues containing modified nucleic acid monomers: thermodynamic, structural and biological effects.

J Med Chem 2019 Feb 8. Epub 2019 Feb 8.

RE31 is a 31-nt DNA aptamer, consisting of the G quadruplex and a duplex domain, which is able to effectively prolong thrombin time. In this paper, we report on our investigations into the influence of certain modified nucleotide residues on thermal stability, folding topology and biological properties of RE31. In particular, the effect of single incorporation of canonical nucleosides in UNA, LNA or β-L-RNA series, was evaluated. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01806
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http://dx.doi.org/10.1021/acs.jmedchem.8b01806DOI Listing
February 2019
3 Reads

Structure-based Design of N-(5-phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors.

J Med Chem 2019 Feb 8. Epub 2019 Feb 8.

Using reported glutathione S-transferase omega 1 (GSTO1-1) co-crystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 µM), compound 18 was synthesized and co-crystalized with GSTO1. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01960
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http://dx.doi.org/10.1021/acs.jmedchem.8b01960DOI Listing
February 2019
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Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.

J Med Chem 2019 Feb 7. Epub 2019 Feb 7.

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti-Wolbachia antibiotics, and as such, may be useful in the treatment of filarial infections caused by Onchocherca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important Neglected Tropical diseases (NTDs) disproportionately impact patients in the developing world. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01854DOI Listing
February 2019

Discovery of Lipophilic Bisphosphonates that Target Bacterial Cell Wall and Quinone Biosynthesis.

J Med Chem 2019 Feb 7. Epub 2019 Feb 7.

We report that alkyl-subsituted bisphosphonates have activity against Bacillus anthracis Sterne (0.40 µg/mL), Mycobacterium smegmatis (1.4 µg/mL), Bacillus subtilis (1. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01878DOI Listing
February 2019
1 Read
5.447 Impact Factor

Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases.

J Med Chem 2019 Feb 5. Epub 2019 Feb 5.

Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01651
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http://dx.doi.org/10.1021/acs.jmedchem.8b01651DOI Listing
February 2019
5 Reads

DDX3X helicase inhibitors as new strategy to fight West Nile Virus infection.

J Med Chem 2019 Feb 5. Epub 2019 Feb 5.

Increased frequency of arbovirus outbreaks in the last ten years represents an important emergence for global health. Climate warming, extensive urbanization of tropical regions and human migrations flows facilitate the expansion of anthropophilic mosquitos and the emerging or re-emerging of new viral infections. Only recently the human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against infectious diseases. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01403DOI Listing
February 2019

Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong , PR China.

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC = 0. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01729DOI Listing
February 2019
3 Reads
5.447 Impact Factor

Novel aryloxyethyl derivatives of 1-(1-benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) phosphorylation-preferring serotonin 5 HT1A receptor biased agonists with robust antidepressant-like activity.

J Med Chem 2019 Feb 5. Epub 2019 Feb 5.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as 'biased agonists' of serotonin 5-HT1A receptors. Compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5 HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, 5-HT2A, histamine H1 and muscarinic M1 receptors, and favorable drug-likeness properties (CNS-MPO, Fsp3, LELP). Read More

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http://dx.doi.org/10.1021/acs.jmedchem.9b00062DOI Listing
February 2019
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3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene and Nonsteroidal Sulfamate Derivatives Inhibit Carbonic Anhydrase IX: Structure-Activity Optimization for Isoform Selectivity.

J Med Chem 2019 Feb 18. Epub 2019 Feb 18.

College of Medicine, Department of Biochemistry and Molecular Biology , University of Florida , Gainesville , Florida 32610 , United States.

3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene (STX140), a bis-sulfamate derivative of the endogenous steroid 2-methoxyestradiol, has shown promising anticancer potency both in vitro and in vivo, with excellent bioavailability. Its activity against taxane-resistant xenografts makes it a potential drug candidate against triple-negative breast cancer (TNBC). These properties are linked to the ability of STX140 to act in a multitargeting fashion in vivo as a microtubule disruptor, leading to cell cycle arrest and with both proapoptotic and anti-angiogenic activities. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01990DOI Listing
February 2019

Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12).

J Med Chem 2019 Feb 5. Epub 2019 Feb 5.

Department of Chemistry , The Scripps Research Institute , 10550 N. Torrey Pines Road , La Jolla , California 92037 , United States.

ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lysophosphatidylserine (lyso-PS) and lysophosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01958DOI Listing
February 2019

3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) derivatives with Potent in vitro and in vivo Antimalarial Activity.

J Med Chem 2019 Feb 4. Epub 2019 Feb 4.

A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 µM, had high in vitro potency against P. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01799DOI Listing
February 2019
5.447 Impact Factor

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

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

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01857DOI Listing
February 2019

Determination of Ligand Binding Epitope Structures Using Polarization Transfer from Hyperpolarized Ligands.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Department of Chemistry , Texas A&M University , 3255 TAMU , College Station , Texas 77843 , United States.

Drug discovery processes require the determination of the protein binding site structure, which can be achieved via nuclear magnetic resonance (NMR) spectroscopy. While traditional NMR spectroscopy suffers from low sensitivity, NMR signals can be significantly enhanced through hyperpolarization of nuclear spins. Here, folic acid is hyperpolarized by dissolution dynamic nuclear polarization (D-DNP). Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01711DOI Listing
February 2019

Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor.

J Med Chem 2019 Feb 11. Epub 2019 Feb 11.

Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.

Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Read More

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http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01483
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http://dx.doi.org/10.1021/acs.jmedchem.8b01483DOI Listing
February 2019
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New Quinolylnitrones for Stroke Therapy: Antioxidant and Neuroprotective ( Z)- N- tert-Butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine Oxide as a New Lead-Compound for Ischemic Stroke Treatment.

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

Laboratory of Medicinal Chemistry , IQOG, CSIC , C/Juan de la Cierva 3 , Madrid 28006 , Spain.

We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen-glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN ( Z)- N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide (23) was shown as a very potent neuroprotective agent. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01987DOI Listing
February 2019

Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 To Produce Analgesia in a Rat Model of Chronic Pain.

J Med Chem 2019 Feb 20. Epub 2019 Feb 20.

Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.

Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01775DOI Listing
February 2019

Suppression of Tumor Growth and Metastases by Targeted Intervention in Urokinase Activity with Cyclic Peptides.

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter , Chinese Academy of Sciences , 155 West Yangqiao Road , Fuzhou , Fujian 350002 , China.

Urokinase-type plasminogen activator (uPA) is a diagnostic marker for breast and prostate cancers recommended by American Society for Clinical Oncology and German Breast Cancer Society. Inhibition of uPA was proposed as an efficient strategy for cancer treatments. In this study, we report peptide-based uPA inhibitors with high potency and specificity comparable to monoclonal antibodies. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01908DOI Listing
February 2019
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Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ.

J Med Chem 2019 Feb 15. Epub 2019 Feb 15.

Institute of Transformative Bio-Molecules , Nagoya University , Nagoya 464-8601 , Japan.

Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01541DOI Listing
February 2019

Phenolic Bis-styrylbenzo[ c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of Aβ Plaque Heterogeneity.

J Med Chem 2019 Feb 13. Epub 2019 Feb 13.

Division of Chemistry, Department of Physics Chemistry and Biology , Linköping University , 581 83 Linköping , Sweden.

A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward Aβ1-42 and Aβ1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to Aβ1-42 fibrils than to Aβ1-40 fibrils. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01681DOI Listing
February 2019

Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140).

J Med Chem 2019 Feb 1. Epub 2019 Feb 1.

κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01679DOI Listing
February 2019
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Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis.

J Med Chem 2019 Feb 1. Epub 2019 Feb 1.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients is primarily driven by hormone-dependent and inflammatory processes - the latter being frequently associated with severe, acute and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and anti-nociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Read More

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http://dx.doi.org/10.1021/acs.jmedchem.8b01862DOI Listing
February 2019
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