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PubMed Journal Database | Journal of medicinal chemistry RSS

16:20 EST 9th December 2016 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 21 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.  BioPortfolio aims to publish relevant information on published papers, clinical trials and news associated with users selected topics.

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Showing PubMed Articles 1–25 of 2,500+ from Journal of medicinal chemistry

Potent Anti-tumor Activities and Structure Basis of the Chiral β-Lactam Bridged Analogue of Combretastatin A-4 Binding to Tubulin.

A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were syn-thesized asymmetrically and evaluated their anti-tumor activities in vitro and in vivo. The co-crystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was firstly identified and demonstrated critically important for th...

Synthesis and antineoplastic evaluation of novel unsymmetrical 1,3,4-oxadiazoles.

A series of novel unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles was synthetized and evaluated for their cytotoxic activity against different cancer cell lines of various origins as in vitro tumor models. Four of 12 new compounds (2b, 2h, 2j and 2l) showed growth inhibitory activity using the XTT dye assay. The most active agent, 2-(2-methyl-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-5-phenyl-1,3,4-oxadiazole, 2j, was chosen for further studies. It showed high potency against a panel of cultured human cancer c...

Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1).

A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellen...

Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Non-tolerance Forming Analgesic Activities.

The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent non-tolerance forming analgesia. In this study, eleven analogs of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogs behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogs produced potent non-tolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesi...

Probing the Complex Binding Modes of the PPARγ Partial Agonist 2-chloro-N-(3-chloro-4-((5-chlorobenzodthiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (T2384) to Orthosteric and Allosteric Sites with NMR Spectroscopy.

In a previous study, a co-crystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an alternate/allosteric site that could alternatively account for the profile. Here, we show ligand aggregation afflicts the activity profile of 1 in biochemical assays. However, ligand-observed ...

Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-regulating Host Chondroitin Sulfate N-acetylgalactosaminyltransferase 1.

There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC50 = 3.17±0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited...

Design, synthesis, and biological evaluation of novel cyclic adenosine-inosine monophosphate (cAIMP) analogs that activate stimulator of interferon genes (STING).

We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine, and that vary by ribose substitution, internucleotide linkage position and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and pro-inflammatory cytokines: for t...

Targeting the Nerve Growth Factor (NGF) Pathway in Drug Discovery. Potential Applications to New Therapies for Chronic Pain.

The neurotrophin nerve growth factor (NGF) has been implicated as a key mediator of chronic pain. NGF binds the tropomysin receptor kinase A (TrkA) and p75, resulting in the activation of downstream signaling pathways that have been linked to pro-nociception. While anti-NGF antibodies have demonstrated analgesia both preclinically and in patients, the mechanism of action of these agents remains unclear. We describe ligands targeting NGF, its receptors, and downstream/related targets. This Perspective highli...

Discovery of Novel Spiro3H-indole-3,2´-pyrrolidin-2(1H)-one Compounds as Chemically Stable, and Orally Active Inhibitors of the MDM2-p53 Interaction.

Scaffold modification based on Wang´s pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3´-pyrrolidin]-2(1H)-one scaffold. Further structure based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interactio...

The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), melatonin, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being ab...

Design, Synthesis and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists.

A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent with an IC50 value of 9.53 nM against the Hh signaling pathway. Complementary mecha...

Probing the ATP-binding pocket of protein kinase DYRK1A with benzothiazole fragment molecules.

DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. Based on the observation of selective DYRK1A inhibition by firefly D-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are ...

Derivatives of 3-amino-2-methylpyridine as BAZ2B Bromodomain Ligands: in silico Discovery and in crystallo Validation.

The 3-amino-2-methylpyridine derivative 1 was identified as ligand of the BAZ2B bromodomain by automatic docking of nearly 500 compounds, selected on the basis of previous fragment hits. Hit expansion by two in silico approaches, pharmacophore search followed by docking, and substructure search resulted in five additional ligands. The predicted binding mode of the six 3-amino-2-methylpyridine derivatives was validated by protein crystallography. A small displacement of residues 1894-1899 of the ZA loop is o...

Radiofluorinated N-Octanoyl Dopamine ((18)FF-NOD) as tool to study tissue distribution and elimination of NOD in vitro and in vivo.

To mitigate pre-transplantation injury in organs of potential donors N-octanoyl dopamine (NOD) treatment might be considered as it does not affect hemodynamic parameters in brain dead (BD) donors. To better assess optimal NOD concentrations for donor treatment, we report on the fast and facile radiofluorination of the NOD-derivative [(18)F]F-NOD [(18)F]5 for in vivo assessment of NOD's elimination kinetics by means of PET imaging. [(18)F]5 was synthesized with reproducible high radiochemical yield and purit...

Hit-to-lead optimization of mouse Trace Amine Associated Receptor 1 (mTAAR1) agonists with a diphenylmethane-scaffold: Design, Synthesis, and biological study.

The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential we rece...

A Bone-Seeking Trans-Cyclooctene for Pretargeting and Bioorthogonal Chemistry: A Proof of Concept Study Using 99mTc- and 177Lu-Labeled Tetrazines.

A high yield synthesis of a novel, small molecule, bisphosphonate-modified trans-cyclooctene (TCO-BP, 2) that binds to regions of active bone metabolism and captures functionalized te-trazines in vivo, via the bioorthogonal inverse electron demand Diels-Alder (IEDDA) cycloaddi-tion, was developed. A 99mTc-labeled derivative of 2 demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound 2 reacted rapidly with a 177Lu-labeled tetrazine in vitro, and pr...

Inhibition of low molecular weight protein tyrosine phosphatase by an induced-fit mechanism.

The low molecular weight protein tyrosine phosphatase (LMW-PTP) is a regulator of a number of signaling pathways and has been implicated as a potential target for oncology and diabetes/obesity. There is significant therapeutic interest in developing potent and selective inhibitors to control LMW-PTP activity. We report the discovery of a novel class of LMW-PTP inhibitors derived from SulfoPhenyl Acetic Amide (SPAA), some of which exhibit greater than 50-fold preference for LMW-PTP over a large panel of PTPs...

Luminescent Ru(II)-phenanthroline complexes as a probe for real-time imaging of Aβ self-aggregation and therapeutic applications in Alzheimer's disease.

The complexes cis-[Ru(phen)2(Apy)2](2+), Apy = 4-aminopyridine and 3,4-aminopyridine are stable in aqueous solution with strong visible absorption. They present emission in the visible region with long lifetime that accumulates in the cytoplasm of Neuro2A cell line without appreciable cytotoxicity. The complexes also serve as mixed-type reversible inhibitors of human AChE and BuChE with high active site contact. cis-[Ru(phen)2(3,4Apy)2](2+) competes efficiently with DMPO by the OH(•) radical. Luminescence...

No Denying It: Medicinal Chemistry Training is in Big Trouble.

There has been little consensus between the pharmaceutical industry and academic communities concerning the best approach to train medicinal chemists for drug discovery. For decades the pharmaceutical industry has shown preference for synthetic organic graduates over candidates with degrees from medicinal chemistry programs on the assumption that medicinal chemistry expertise will be acquired on the job. However, ongoing changes to pharmaceutical drug discovery organizations and practices threaten to underm...

Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor Following Structure-Based Fragment Optimization.

Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of: i) the amine-binding region, ii) the upper and lower aromatic region and iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines....

β-Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences.

In this study inspired by previous work on 3-substituted Asp analogues, we designed and synthesized a total of 32 β-sulfonamide Asp analogues and characterized their pharmacological properties at the excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3. In addition to several potent EAAT inhibitors displaying IC50 values ∼1 μM at all three subtypes, this elaborate structure-activity relationship also identified analogues exhibiting distinct preferences or selectivities for specific transpo...

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing ...

Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study.

Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subs...

A novel Parkinson's disease drug candidate with potent anti-neuroinflammatory effects through the Src signaling pathway.

Numerous drug treatments are available for Parkinson's disease (PD), an age-related neurodegenerative disease, but most cause serious side effects. Therefore, novel therapeutic strategies that halt disease progression and allow for long-term administration are urgently needed. Neuroinflammation critically contributes to the pathogenesis of PD. Here, we report the discovery and optimization of phloroglucinol derivatives, a novel class of anti-neuroinflammatory compounds. Structural modifications of the hit c...

The Oncolytic Efficacy and in Vivo Pharmacokinetics of 2-(4-Chlorophenyl)quinolin-4-yl(piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features.

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the pre...


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