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00:14 EDT 2nd September 2014 | BioPortfolio

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

Tuesday 6th October 1056

Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists.

Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G protein-coupled receptor. This target has attracted much interest as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutic...


Discovery of a Selective, Substrate-competitive Inhibitor of the Lysine Methyltransferase SETD8.

The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only known selective...


Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor.

We previously reported the discovery of 4-aryl substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this paper we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. Fine-tuning of metabolism and hERG followed by differentiation of advanced leads identified based on PK profiles and i...

Thursday 14th November 1055

A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs.

A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxido platinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic and cyclobutanedicarboxylic acid was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FT...

Saturday 20th July 1055

Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14α-Demethylase: Two Regions of the Enzyme Molecule Potentiate its Inhibition.

Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity and antiparasitic potencies of a new set of -phen...


Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake and cytotoxicity of a series of carboranylporphyrin conjugates.

A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and peptide Tyr-D-Arg-Phe-β-Ala (TAPA) were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells as model, and their cytotoxicity and uptake in human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized and its...

Wednesday 6th December 1053

First Photoswitchable Neurotransmitter Transporter Inhibitor: Light-induced Control of γ-Aminobutyric Acid Transporter 1 (GAT1) Activity in Mouse Brain.

Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be associated with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradiation with light as...

Saturday 16th September 1053

Discovery of 1H-indole-2-carboxamides as Novel Inhibitors of the Androgen Receptor Binding Function 3 (BF3).

To overcome resistance to conventional antiandrogens of human androgen receptor (AR), the allosteric site of the AR binding function 3 (BF3) was investigated as an alternative target for small molecule therapeutics. A library of 1H-indole-2-carboxamides were discovered as BF3 inhibitors and exhibited strong anti-proliferative activity against both LNCaP and Enzalutamide-resistant prostate cancer cell lines. Several of the lead compounds may prove of particular benefit as a novel alternative treatment for ca...

Saturday 15th July 1053

Synthesis, Antimitotic and Antivascular Activity of 1-(3',4',5'-Trimethoxybenzoyl)-3-Arylamino-5-Amino-1,2,4-Triazoles.

A new class of compounds that incorporated the structural motif of the 1-(3',4',5'-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole molecular skeleton was synthesized and evaluated for their antiproliferative activity in vitro, interactions with tubulin and cell cycle effects. The most active agent, 3c, was evaluated for antitumor activity in vivo. Structure-activity relationships were elucidated with various substituents on the phenyl ring of the anilino moiety at the C-3 position of the 1,2,4-triazol...

Tuesday 25th April 1053

New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity as Anticancer Agents including Hedgehog-dependent Cancer.

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5 MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog s...

Tuesday 21st March 1053

Studies examining the relationship between the chemical structure of Protoxin II and its activity on Voltage Gated Sodium Channels.

The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin is comprised of a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.7 and Nav1.2 chann...

Friday 3rd February 1053

Anti-HIV Activities of Precisely Defined, Semi-rigid, Carboxylated Alternating Copolymers.

Di-tert-butyl (E)-4,4'-stilbenedicarboxylate and tert-butyl 4-vinylbenzoate were copolymerized with maleic anhydride and tert-butyl 4-maleimidobenzoate, individually and respectively. After conversion into polyanions, these four copolymers exhibited activity against four HIV-1 strains: IIIb, BaL, JR-CSF, and 92UG037. For both the IIIb and BaL HIV-1 strains, the lowest IC50 (0.095 and 0.23 μg/mL, respectively) values were obtained with poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA). For JR-...


A Method for the Evaluation of Structure-Activity Relationship Information Associated with Coordinated Activity Cliffs.

Activity cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity cliffs focuses on compound pairs, the vast majority of cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity cliffs, which often also overlap. In activity cliff networks, coordinated cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bi...

Sunday 28th April 1049

Structure-based design of either β1i or β5i specific inhibitors of human immunoproteasomes.

Mammalian genomes encode seven catalytic proteasome subunits, namely β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes) and the thymoproteasome-specific subunit, β5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of β1c/β1i,...


Structural Basis for HTLV-1 Protease Inhibition by the HIV-1 Protease Inhibitor Indinavir.

HTLV-1 protease (HTLV-1 PR) is an aspartic protease which represents a promising drug target for the discovery of novel anti-HTLV-1 drugs. The X-ray structure of HTLV-1 PR in complex with the well-known and approved HIV-1 PR inhibitor Indinavir was determined at 2.40 Å resolution. In this contribution, we describe the first crystal structure in complex with a nonpeptidic inhibitor that accounts for rationalizing the rather moderate affinity of Indinavir against HTLV-1 PR and provides the basis for further ...


Modification and Biological Evaluation of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion.

Fascin has recently emerged as a potential therapeutic target as its expression in cancer cells is closely associated with tumor progression and metastasis. Following the initial discovery of a series of thiazole derivatives that demonstrated potent anti-migration and anti-invasion activities via possible inhibition of fascin function, we report here the design and synthesis of 63 new thiazole derivatives by further structural modifications in search of more potent fascin inhibitors. The 5 series of analogs...


N-aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial lead compounds.

From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 hours) in rat blood. ...


Structure based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared...


Optimization of potent DFG-in inhibitors of Platelet Derived Growth Factor Receptorβ (PDGF-Rβ) guided by water thermodynamics.

In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones towards potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC50 = 0.5 µM). Furthermore, 2 was shown to be selective for PDGF-Rβ in a panel of ...


111In-DOTALTT-SS28, a first pansomatostatin radioligand for in vivo targeting of somatostatin receptor-positive tumors.

Radiolabeled pansomatostatin-like analogs are expected to enhance the diagnostic sensitivity and to expand the clinical indications of currently applied sst2-specific radioligands. In this study, we present the somatostatin mimic [DOTA]LTT-SS28 ([(DOTA)Ser1,Leu8,DTrp22,Tyr25]SS28) and its 111In-radioligand. [DOTA]LTT-SS28 showed pansomatostatin-like profile binding with high affinity to all five hsst1-5 (IC50 values in the lower nM-range). Furthermore, [DOTA]LTT-SS28 behaved as an agonist at hsst2, hsst3 an...


Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20(S)-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents.

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the AT...


Substituted N-(Biphenyl-4'-yl)methyl (R)-acetamido-3-methoxypropionamides: Potent anticonvulsants that affect frequency (use)-dependence and slow inactivation of sodium channels.

We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent po...


Development and Biological Evaluation of Potent and Selective c-KITD816V Inhibitors.

The c-KIT tyrosine kinase has emerged as a potential therapeutic target for an array of diseases. However, there exists a drug resistance that is caused by mutations in c-KIT; therefore, c-KIT remains as a clinical challenge due to limited effective treatment options for therapies. For example, the acquired activating point mutation D816V significantly impairs the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular level will aid in designing and developin...


Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit.

Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excel...


Correction to Inhibiting the HIV Integration Process: Past, Present, and the Future.

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