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PubMed Journal Database | Journal of medicinal chemistry RSS

07:11 EDT 24th May 2019 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 29 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.

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For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 1,200+ from Journal of medicinal chemistry

N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy) benzodthiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships and In Vivo Efficacy.

Necroptosis, a form of programmed cell death, plays a critical role in various diseases, including inflammato-ry, infectious and degenerative diseases. We previously identified TAK-632 (6) as a potent inhibitor of necrop-tosis by targeting both RIPK1 and RIPK3 kinases. Herein, we performed three rounds of structural optimizations of TAK-632 and elucidated structure-activity relationships to generate more potent inhibitors by targeting RIPK3. The analogues with carbamide groups exhibited great anti-necroptot...

Covalent Inhibitors of Protein-Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues.

We have recently reported on a series of Lys-covalent agents targeting the BIR3 domain of the X-linked Inhibitor of Apoptosis Protein (XIAP) using a benzamide-sulfonyl fluoride warhead. Using XIAP as a model system, we further investigated a variety of additional warheads that can be easily incorporated into binding peptides, and analyzed their ability to form covalent adducts with lysine and other amino acids, including tyrosine, histidine, serine, and threonine, using biochemical and biophysical assays. M...

Revealing the mechanism of agonist-mediated cannabinoid receptor 1 (CB1) activation and phospholipid-mediated allosteric modulation.

Cannabinoid receptor 1 (CB1) mediates the functional responses of Δ-tetrahydrocannabinol (Δ-THC). Although progress has been made in understanding cannabinoid binding and receptor activation, detailed knowledge of the dynamics involved in the activation mechanism of CB1 is lacking. Here, we use recently determined CB1 crystal structures to analyze its transition from inactive to active state by performing unbiased microsecond-length molecular dynamics (MD) simulations, totaling 32 μs, with and without bo...

CF2H, a Functional Group Dependent Hydrogen Bond Donor: Is it a More or Less Lipophilic Bioisostere of OH, SH and CH3?

The effects of the CF2H moiety on H-bond acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers or electron withdrawing groups, are discussed. It was found that the CF2H group acts as a HB-donor with a strong dependence on the attached functional group (A = 0.035-0.165). Regarding the lipophilicity, the CF2H group may acts as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and C...

Conjugation of short peptides to dibenzodiazepinone-type muscarinic acetylcholine receptor ligands determines MR selectivity.

Muscarinic acetylcholine receptors (MRs), comprising five subtypes (MR-MR) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly MR-selective MR antagonists based on the conjugation of di- or tripeptides to MR-preferring dibenzodiazepinone-type MR antagonists. MR selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved MR s...

On the Process of Discovering Leads that Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.

Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in massive accumulation of neutrophil elastase resulting in lung degradation and death. The current CF therapy relies on inhaled deoxyribonuclease and hypertonic saline, but does not address elastolytic degradation of the lung. We reasoned that allosteric agents targeting the heparin-binding site of neutrophil elastase would offer a therapeutic paradigm. Screening a library of 60 non-saccharide glycosaminoglycan mimeti...

Rational design of 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of intra- and inter-molecular polar interactions of a new ataxia telangiectasia mutated and Rad3-related (ATR) kinase inhibitor.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of...

Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC).

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene t...

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that crosslinks collagens and elastin in the extracellular matrix (ECM) and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High throughput screening (HTS) provided the initial hits. Stru...

Antibiotic adjuvants: Make antibiotics great again!

Multiple approaches have been developed to combat bacterial resistance. However, the combination of antibiotic resistance mechanisms by bacteria and the limited number of effective antibiotics available, decreases the effective interventions for the treatment of current bacterial infections. This review covers the many ways that bacteria resist antibiotics including antibiotic target modification, the use of efflux pumps and antibiotic inactivation. As a pertinent example, the use of beta lactamase inhibito...

Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization.

A promising design paradigm for small-molecule inhibitors of tubulin polymerization that bind to the colchicine site draws structural inspiration from the natural products colchicine and combretastatin A-4 (CA4). Our previous studies with benzocycloalkenyl and heteroaromatic ring systems yielded promising inhibitors with dihydronaphthalene and benzosuberene analogues featuring phenolic (KGP03 and KGP18) and aniline (KGP05 and KGP156) congeners emerging as lead agents. These molecules demonstrated dual mecha...

Synthesis of Shld derivatives, their binding the Destabilizing Domain and influence on protein accumulation in transgenic plants.

A series of 35 analogues of Shld with modifications in the A-residue and the C-residues were prepared and investigated for binding to FKBP and GFP accumulation in transgenic plants. The modifications investigated explored variations that was supposedly inside or outside the receptor binding site with the latter being important by influencing the overall polarity of the compounds in order to improve the absorption in plants. The binding of the new compounds to the destabilizing domain was determined using a ...

Design and Discovery of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (LXH254)- A selective, efficacious and well-tolerated RAF inhibitor targeting RAS mutant cancers: The path to the clinic.

Direct pharmacological inhibition of RAS has remained elusive and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254)1, a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound 3 (RAF709), a was potent, selective, efficacious, and well-tolerated in preclinical models, but ...

Substituted Pyridazin-3(2H)-ones as Highly Potent and Biased Formyl Peptide Receptors Agonists.

Herein we describe the development of a focused series of functionalized pyridazin-3(2H)-one-based formyl peptide receptors (FPR) agonists which demonstrate high potency and biased agonism. The compounds described demonstrated biased activation of pro-survival signaling - ERK1/2 phosphorylation - through diminution of the detrimental FPR1/2-mediated intracellular calcium (Cai2+) mobilization. Compound 50 showed an EC50 of 0.083 µM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Cai2...

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.

Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synt...

Modification and biological evaluation of a series of 1,5-diaryl-1,2,4-triazole compounds as novel agents against pancreatic cancer metastasis through targeting myoferlin.

Pancreatic cancer is one of the most common cancers with extremely low survival rate. Metastasis, as one of the key reasons of cancer related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent anti-metastatic agents. Lead compound 6y displayed effective anti-metastatic activities in pancreatic cancer in vitro and in vivo. Conc...

Rapid Telomere Reduction in Cancer Cells Induced by G-Quadruplex-Targeting Copper Complexes.

Telomere length determines the replicative capacity of mammalian cells. Successive telomere reduction to a critically short length can lead to cellular senescence that irreversibly prevents cells from further cell division. A series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity towards G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually ...

Discovery of Potent, Selective and Short-Acting Peptidic V Receptor Agonists.

The vasopressin analogue desmopressin (dDAVP, 1) is a potent V receptor agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis and hyponatremia. In search of novel, potent, selective and short-acting peptidic VR agonists, we synthesized a series of C-terminally truncated analogues of ...

Pharmacological Chaperones for the Treatment of α-Mannosidosis.

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM causative mutations compromise enzyme folding and could be rescue with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5N,6O-oxomethylidenemannonojirimycin (OMJ) glycomimetic core and different aglycones, in either mono or multivalent displays, elicit b...

Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform Na1.7.

Voltage-gated sodium ion channel subtype 1.7 (Na1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional Na1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism aro...

Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effe...

Discovery and Lead-optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis and ulcerative colitis, and neuro-logical diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this paper we report on the design of potent and hig...

Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug.

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal a...

Discovery of Potent, Selective, and Brain-Penetrant 1 Η-Pyrazol-5-yl-1Η -pyrrolo2,3- bpyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors.

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization guided by a cocrystal structure of compound 1 bound to ALK resulted in the ide...

Correction to Synthesis of C-Labeled RXR Partial Agonist 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)aminobenzotriazole-5-carboxylic Acid (CBt-PMN) by Direct CCarbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof.


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