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02:19 EDT 23rd September 2014 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,700+ from Journal of medicinal chemistry

Sunday 27th June 1074

ST7612AA1, a thioacetate-ω (γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors.

A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the omega position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC i...


Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1/UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer.

Deregulation of ubiquitin conjugation or deconjugation has been implicated in the pathogenesis of many human diseases including cancer. The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1), in association with UAF1 (USP1-associated factor 1), is a known regulator of DNA damage response and has been shown as a promising anticancer target. To further evaluate USP1/UAF1 as a therapeutic target, we conducted a quantitative high throughput screen of >400000 compounds and subsequent medicinal chemistr...


Phenyl substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: Inhibitors of influenza A endonuclease.

Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is attractive for the development of new agents for the treatment of influenza infection. Our earlier studies identified a series of 5- and 6-phenyl substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors of influenza endonuclease. These agents identified as bimetal chelating ligands binding to the active site of the enzyme. In the pr...

Saturday 20th September 1072

Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38.

Cyclic adenosine 5'-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5'-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the non-essential nature of the "southern" ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs a...

Thursday 24th April 1072

Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor.

Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A...


Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease.

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol...


Development of inhibitors of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway enzymes as potential anti-infective agents.

Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively, and plants, utilize the 2C-methyl-D-erythritol-4-phosphate (MEP, 5) pathway for the biosynthesis of isopentenyl diphosphate (1) and dimethylallyl diphosphate (2), the universal precursors of isoprenoids while humans exclusively utilize the alternative mevalonate pathway for the synthesis of 1 and 2. This distinct distribution, together with the fact that the MEP p...

Monday 10th February 1067

C-glycoside Mimetics Inhibit Glioma Stem Cell, Proliferation, Migration and Invasion.

This paper reports the design and synthesis of C-glycoside mimetics (D-glycero-D-talo- and D-glycero-D-galactopyranose analogues) subset of the recently published phostines, belonging to the [1,2]-oxaphosphinane core. Eighteen new compounds have been tested against eleven cancer cell types belonging to six categories of tumoral tissues and three different species. The hit compound 5.3d inhibited invasion and migration on fibronectin, vitronectin and laminin on both GBM stem cells (Gli7 and Gli4) and GBM can...


Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Towards the Development of Novel Antimalarial Agents.

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy,...


Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells.

Class III β-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of forty-four 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. Th...


Peptides containing beta-amino acid patterns-challenges and successes in medicinal chemistry.

The construction of bioactive peptides using β-amino acid containing sequence patterns is a very promising strategy to obtain analogs that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of native peptides. They can be either combined with α-amino acids by following specific patterns, which results in backbone architectures with well-defined orientations of the side-chain functio...

Tuesday 30th April 1066

Desferrithiocin: A Search for Clinically Effective Iron Chelators.

The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design op...


Discovery of 5-Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119.

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabet...


Synthesis and biological evaluation of novel millepachine derivatives as a new class of tubulin polymerization inhibitors.

Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro anti-proliferative activity. Among them, 8 exhibited the most potent activity with IC50 values of 8-27 nM against panel of cancer cell lines and retained full activity in multidrug resistant cancer cells. Treated cells were arrested in G2/M phase and resulted in cellular apoptosis. Microtubule dynamics confirmed 8 was a novel tubulin polymerization inhibitor by binding at the colchicine site. 8 also exhibited anti...

Tuesday 18th September 1065

Discovery of 2-Pyridyl Ureas as Glucokinase Activators.

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimizati...

Wednesday 20th June 1065

In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs.

Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and CNS dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this dom...



Antibody-drug conjugate (ADCs) have a significant impact towards the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for non-hodgkin lymphoma and trastuzumab emtansine (trastuzumab-MCC-DM1), for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugating DM1 to trastuzumab the safety was improved and cli...

Thursday 2nd December 1063

Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1δ and ε with nanomolar inhibitory activity on cancer cell proliferation.

Deregulation of CK1 (Casein Kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-specific inhibitor compound with significant effects on several tumor cell lines was further modified to difluoro-dioxolo-benzoimidazole derivatives displaying remarkable inhibitory effects and in...

Tuesday 16th February 1063

Exploring the Scaffold Universe of Kinase Inhibitors.

The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic criteria into account. Scaffold coverage varied greatly across the kinome, and many scaffolds representing compounds with different activity profiles were identified. The majority of kinase inh...


Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds.

Toll-like receptor (TLR)-7 and -8 agonists are potential vaccine adjuvants, since directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing 'heuristics' to define structural requisites governing activity at TLR7 ...


Structure-guided, single-point modifications in the phosphinic dipeptide structure yield highly potent and selective inhibitors of neutral aminopeptidases.

Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor-enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate ...


"New Drug" Designations for New Therapeutic Entities: New Active Substance, New Chemical Entity, New Biological Entity, New Molecular Entity.

This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active subst...

Wednesday 2nd July 1061

Structural evidence of N-6 isopentenyladenosine as a new ligand of farnesyl pyrophosphate synthase.

N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family has shown in human many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase activity. To investigate the relationship between i6A and farnesyl pyrophosphate synthase (FPPS), we undertook an inverse virtual screening computational target searching, testing i6A on a large panel of 3D protein structures involved in cancer processes. Experimentally, we performed an N...


2013 Philip S. Portoghese Medicinal Chemistry Lectureship: Drug Discovery Targeting Allosteric Sites.

The identification of sites on receptors topographically distinct from the orthosteric sites, so-called allosteric sites, has heralded novel approaches and modes of pharmacology for target modulation. Over the past 20 years, our understanding of allosteric modulation has grown significantly, and numerous advantages, as well as caveats (e.g., flat structure-activity relationships, species differences, 'molecular switches'), have been identified. For multiple receptors and proteins, numerous examples have bee...


Acidic & Basic Drugs in Medicinal Chemistry: A Perspective.

The acid/base properties of a molecule are among the most fundamental for drug action. However, they are often overlooked in a prospective design manner unless it has been established that a certain ionization state (e.g. quaternary base or presence of a carboxylic acid) appears to be required for activity. In medicinal chemistry optimization programs it is relatively common to attenuate basicity to circumvent undesired effects such as lack of biological selectivity or safety risks such as hERG or phospholi...

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