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PubMed Journal Database | Journal of medicinal chemistry RSS

08:11 EDT 28th September 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.

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

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

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...

Nucleoside derived antibiotics to fight microbial drug-resistance: New Utilities for an Established Class of Drugs?

Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid and protein biosynthesis. Nucleoside analogues have also been shown to ...

Discovery of an Orally Bioavailable Gonadotropin-releasing Hormone (GnRH) Receptor Antagonist.

We developed a compound library for orally available gonadotropin-releasing hormone (GnRH) receptor antagonists that were based on a uracil scaffold. Based on in vitro activity and CYP inhibition profile, we selected 18a (SKI2496) for further in vivo studies. Compound 18a exhibited more selective antagonistic activity toward the human GnRH receptors over the GnRHRs in monkeys and rats, and this compound also showed inhibitory effects on GnRH-mediated signaling pathways. Pharmacokinetic and pharmacodynamic e...

A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity.

Side effects and acquired resistance by cancer cells limit the use of Platinum (Pt) anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanopartic...

Amending HIV drugs: a novel small-molecule approach to target lupus anti-DNA antibodies.

Systemic lupus erythematosus is an autoimmune disease that can affect numerous tissues and is characterized by the production of nuclear antigen-directed autoantibodies (e.g. anti-dsDNA). Using a combination of virtual and ELISA-based screens, we made the intriguing discovery that several HIV-protease inhibitors can function as decoy antigens to specifically inhibit the binding of anti-dsDNA antibodies to target antigens such as dsDNA and pentapeptide DWEYS. Computational modeling revealed that HIV-protease...

Enabling efficient PET imaging of Synaptic Vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent (18)F-labelled ligand ((18)FUCB-H).

We herein describe the straightforward synthesis of a stable pyridyl(4-methoxyphenyl)iodonium salt and its [(18)F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [(18)F]UCB-H, a PET tracer for the imaging of Synaptic Vesicle glycoprotein 2A (SV2A). Over the course of one year, 40 automated productions provided 34±2% of injectable [18F]UCB-H from up to 285 GBq (7.7 Ci) of [(18)F]fluoride in 50 minutes (uncorrected radiochemical yield. Specific Activity = 815±185 GBq/...

Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes.

Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective non-covalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide...

Unusual Amino Acids in Medicinal Chemistry.

Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalised amine and carboxyl groups attached to a chiral center group along with one or two potentially diverse side chains provides a unique three-dimensional structure with high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs...

Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist Ac-D-Tyr-Hyp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448) with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility.

Metastin/kisspeptin is an endogenous ligand of KISS1R. Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of GnRH and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-D-Tyr-D-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed an extr...

Virtual screening and X-ray crystallography Identify non-substrate analog inhibitors of Flavin-dependent Thymidylate Synthase.

Thymidylate synthase-X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima ThyX in complex with a non-substrate analog inhibitor. Given the active site similarities between Mtb-ThyX and Tm-ThyX, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as scaffo...

Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.

Well-characterized selective inhibitors of protein arginine methyltransferases (PRMTs) are invaluable chemical tools for testing biological and therapeutic hypotheses. Based on 4, a fragment-like inhibitor of type I PRMTs, we conducted structure-activity relationship (SAR) studies and explored three regions of this scaffold. The studies led to the discovery of a potent, selective and cell-active dual inhibitor of PRMT4 and PRMT6, 17 (MS049). As compared to 4, 17 displayed much improved potency for PRMT4 and...

Truncated auto-inducing peptides as antagonists of Staphylococcus lugdunensis quorum sensing.

Competitive quorum sensing antagonisim (QS) offers a novel strategy for attenuating current multi-drug resistant staphylococcal infections. To this end, a series of 10 truncated analogues based on the parent auto-inducing peptides (AIPs) of Staphylococcus lugdunensis (group I & II) and Staphylococcus epidermidis (groups I - III) were sequentially assessed against a newly developed Staphylococcus lugdunensis group I QS reporter strain. The truncated analogues based upon Staphylococcus lugdunensis AIP-1 (1) a...

Preparation, antiepileptic activity and cardiovascular safety of dihydropyrazoles as brain-penetrant T-type calcium channel blockers.

A series of dihydropyrazole derivatives was developed as potent, selective, brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized non-convulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-(4-(2,4-difluorophenyl)-1-piperazinyl)methyl-1,2,4-triazolo4,3-apyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 receptor Positive Allosteric Modulator (PAM).

Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the last decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good drug-like properties has remained elusive, in part because of the hydrophobic natu...

Discovery and optimization of N-(4-(3-aminophenyl)thiazol-2-yl)acetamide as a novel scaffold active against sensitive and resistant cancer cells.

Cancer is the second cause of deaths worldwide and is forecasted to affect more that 22 million people in 2020. Despite dramatic improvement in its care over the last two decades, the treatment of resistant forms of cancer is still an unmet challenge. Thus, innovative and efficient treatments are still needed. In this context, we report herein the synthesis and the evaluation of a new class of bioactive molecules belonging to the N-(4-(3-aminophenyl(thiazol-2-yl)acetamide family. Structure-activity relation...

The rational design, synthesis and antimicrobial properties of thiophene derivatives that inhibit bacterial histidine kinases.

The emergence of multi-drug-resistant bacteria emphasizes the urgent need for novel antibacterial compounds targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved adenosine triphos...


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