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PubMed Journal Database | Journal of medicinal chemistry RSS

06:31 EDT 30th June 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 2,400+ from Journal of medicinal chemistry

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compou...

Discovery of 3-(5'-Substituted)-benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis and Biological Evaluation.

Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this paper, we described the identification of the potent pan-FGFR inhibitor (R)-23 (FGFR1-4 IC50 values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (R)-23 exhibited excellent in vitro inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analy...

Searching for new leads for Tuberculosis: Design, synthesis and biological evaluation of novel 2-quinolin-4-yloxyacetamides.

In this study, a new series of more than sixty quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity and an improved physicochemical profile ...

Jatrophane Diterpenoids as Modulators of P-Glycoprotein-Dependent Multidrug Resistance (MDR): Advances of Structure-Activity Relationships and Discovery of Promising MDR Reversal Agents.

The phytochemical study of Pedilanthus tithymaloides led to the isolation of 13 jatrophane diterpenoids (1-13), of which eight (1-8) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (14-35). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemo...

Fatty acid amide hydrolase (FAAH), acethylcholinesterase (AChE) and butyrylcholinesterase (BuChE): networked targets for the development of carbamates as potential anti Alzheimer's Disease agents.

The modulation of the endocannabinoid system is emerging as viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neurodegenerative disorders such as Alzheimer's disease, effectively preventing or slowing the progression of the disease. Hence, in the search for a more effective treatment for Alzheimer's disease,...

Development of an Orally Available and Central Nervous System (CNS)-Penetrant Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-à-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses anti-toxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human Ether-à-go-go-Related Gene (hERG) inhibitory activity, associated with long Q-T syndrome-which presents a cardiotoxicity risk. Here...

Discovery and Structure Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-Phosphate (S1P1).

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carb...

1,2-Benzisothiazole Derivatives Bearing 4-, 5- or 6-alkyl/arylcarboxamide Moieties Inhibit Carbonic Anhydrase Isoform IX (CAIX) and Cell Proliferation under Hypoxic Conditions.

Three novel series of 1,2-benzisothiazole derivatives have been developed as inhibitors of carbonic anhydrase isoform IX. Compounds 5c and 5j, tested in vitro on the human colon cell line HT-29, blocked the growth of cells cultured un-der chemically-induced hypoxic conditions, displaying a specific activity against cancer cells characterized by CAIX up-regulation. Moreover, a synergistic activity of 5c with SN38 (the active metabolite of irinotecan) and 5-fluorouracil on cell proliferation under hypoxic con...

Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo4,5-bpyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.

The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The co-crystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2 and AKT3, as well as potent cellu...

The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.

Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the 1) coplanarity of the three carbon atoms, 2) relatively shorter (1.51 Å) C-C bonds, 3) enhanced pi-character of C-C bonds, and 4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs conta...

Identification and SAR evaluation of hemozoin-inhibiting benzamides active against Plasmodium falciparum.

Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe(III)PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adop...

Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach.

The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective Neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors, and as a lead compound for anti-obesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labelled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)- diaminosuberoyl containing peptide, (R,R)-1 had markedly higher affini...

Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine.

"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qualitative and quantitative study of metabolites. This emerging field is clearly linked to g...

Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable pan-Pim Kinase Inhibitors.

The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for...

Indole-2-carboxamide-Based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection.

Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity both at an in vitro and in vivo level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work we now further elaborate on the SAR of these compounds which has led in turn to the identification of a new analog, ...

Discovery of the potent and selective M1 PAM-agonist N-(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl-5-methyl-4-4-(1,3-thiazol-4-yl)benzylpyridine-2-carboxamide (PF-06767832): Evaluation of efficacy and cholinergic side effects.

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with non-selective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and...

Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the Ataxia Telangiectasia Mutated (ATM) Kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with over...

Benzylpiperidine-linked diarylthiazoles as potential anti-Alzheimer's agents-synthesis and biological evaluation.

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multi-target-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anti-cholinesterase (anti-ChE) activity; the most potential compound (44) among them showing the highest activity (IC50 value: 0.30±0.01 µM) for AChE and (1.84±0.03 µM) for BuChE. The compound (44) showed mixed inhib...

Monothiocarbamates strongly inhibit carbonic anhydrases in vitro and possess intraocular pressure lowering activity in an animal model of glaucoma.

A series of monothiocarbamates (MTCs) were prepared from primary/secondary amines and COS, as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, using the dithiocarbamates, the xanthates and the trithiocarbonates as lead compounds. The MTCs effectively inhibited the pharmacologically relevant human (h) hCAs isoforms I, II, IX and XII in vitro, and showed KIs spanning between the low and medium nanomolar range. By means of a computational study the MTC moiety binding mode on the CAs was explained. Fur...

A Selective and Slowly Reversible Inhibitor of L-Type Amino Acid Transporter 1 (LAT1) Potentiates Anti-Proliferative Drug Efficacy in Cancer Cells.

The L-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is over-expressed in several types of tumors and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (1), which inhibited the uptake of LAT1 substrate, L-leucin as well as cell growth. It also significantly potentiated the ef...

Discovery of new chemical entities for old targets: insights on the lead optimization of chromone-based monoamine oxidase B (MAO-B) inhibitors.

The discovery of new chemical entities endowed with potent, selective and reversible monoamine oxidase-B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in...

Uncoupling the structure-activity relationships of β2 adrenergic receptor ligands from membrane binding.

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity (e.g. Kd). Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane an...

β-Lactamases: Why and How.

The targets of β-lactam antibiotics are bacterial DD-peptidases that catalyze the final steps of peptidoglycan biosynthesis. Bacterial resistance to β-lactams is achieved by the production of β-lactamases, enzymes that catalyze β-lactam hydrolysis. Structural studies of both of these groups of enzymes, their substrates and of β-lactams have led to the conclusion that β-lactamases have evolved from a DD-peptidase ancestor. Thus, the active sites of DD-peptidases and serine β-lactamases are very simila...

Benzyl (11)CHippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compoun...

Tetrahydroisoquinoline-derived urea and 2,5-diketopiperazine derivatives as selective antagonists of the transient receptor potential melastatin 8 (TRPM8) channel receptor and anti-prostate cancer agents.

Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more...


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