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14:41 EST 1st February 2015 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,900+ from Journal of medicinal chemistry


3,4-Diaminobenzoic Acid Derivatives as Inhibitors of the Oxytocinase Subfamily of M1 Aminopeptidases with Immune-Regulating Properties.

Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a s...


Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1~2% of lung adenocarcinomas (LADCs) in late 2011. Several related clinical trials for non-small cell lung cancer (NSCLC) with KIF5B-RET rearrangements have been swiftly initiated by the discovery of KIF5B-RET fusion gene using existing RET inhibitors such as lenvatinib, vandetanib, sunitinib, ponatinib, cabozatinib, and AUY922. Anti-RET activity and their st...


Overcoming Mutagenicity and Ion Channel Activity: Optimization of Selective Spleen Tyrosine Kinase Inhibitors.

Development of a series of highly kinome selective Spleen Tyrosine Kinase (Syk) inhibitors with favorable drug-like properties is described. Early leads were discovered through X-ray crystallographic analysis and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including logD, PSA, and pKa. PSA proved most effective for ...


Discovery of Imidazo1,2-bpyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity.

Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-...


Bis-Aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors.

The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 µM), and good in vitro and in vivo pharmacokinetic ...

Saturday 6th November 1153

Antitumor Sulfonylhydrazines: Design, Structure-Activity Relationships, Resistance Mechanisms, and Strategies for Improving Therapeutic Utility.

1,2-Bis(sulfonyl)-1-alkylhydrazines (BSHs) were conceived as more specific DNA guanine O-6 methylating and chloroethylating agents lacking many of the undesirable toxicophores contained in antitumor nitrosoureas. O(6)-Alkylguanine-DNA alkyltransferase (MGMT) is the sole repair protein for O6-alkylguanine lesions in DNA, and has been reported to be absent in 5-20 % of most tumor types. Many BSHs exhibit highly selective cytotoxicity towards cells with little or no MGMT activity. The development of clinically...

Thursday 2nd April 1152

Novel 5-Substituted Pyrrolo2,3-dpyrimidines as Dual Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase and as Potential Antitumor Agents.

ABSTRACT A new series of 5-substituted thiophenyl pyrrolo[2,3-d]pyrimidines 6-11 with varying chain lengths (n = 1-6) was designed and synthesized as hybrids of the clinically used anticancer drug pemetrexed (PMX) and our 6-substituted thiophenyl pyrrolo[2,3-d]pyrimidines 2c and 2d with folate receptor (FR) α and proton-coupled folate transporter (PCFT) uptake specificity over the reduced folate carrier (RFC) and inhibition of de novo purine nucleotide biosynthesis at glycinamide ribonucleotide formyltrans...


Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase Open New Prospects for the Treatment of Neurological Disorders.

The disubstituted pyrimidines based SAR study by Silverman et al. ( J. Med. Chem. 2014 , DOI: 10.1021/jm501719e ) was focused on improving bioavailability and physicochemical properties of the designed inhibitors while retaining the potency for neural nitric oxide synthase (nNOS) and selectivity over the other two nitric oxide synthase (NOS) isoforms (endothelial NOS and inducible NOS). One of the new promising lead compounds, compound 7, displayed nanomolar potency for nNOS (Ki = 19 nM), good selectivity o...


Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.

Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed to the compounds for the combination of antioxidant activity and strengthening the ability fighting against the diabetic complications. Most of the series 6 showed potent and selective effect on the ALR2 inhibition with IC50 values in the range of 0.032 - 0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro -2-oxoquinoxalin-1(2H)-yl)acetic aci...


A series of novel terpyridine-skeleton molecule derivants inhibit tumor growth and metastasis by targeting topoisomerases.

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-b]pyridine core and 15 comprising chromeno[4,3-b]pyridine core, were synthesized, and their biological activities were evaluated. Compound 8 was determined to be a non-intercalative topo I and II dual catalytic inhibitor and compound 22, a non-intercalative topo II specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in ...


(Dis)similar analogues of riboswitch metabolites as antibacterial lead compounds.

The rise of antimicrobial resistance in human pathogenic bacteria increases the urge for the discovery of novel yet unexplored antibacterial drug targets. In this way, riboswitches, which are embedded in untranslated regions of bacterial messenger RNA, represent such an interesting target structure. These RNA elements regulate gene expression upon binding to natural metabolites with high affinity and in a highly discriminative manner. Recently, effort has been placed on the identification of artificial ribo...

Tuesday 10th September 1151

Discovery of Highly Potent, Selective and Efficacious Small Molecule Inhibitors of ERK1/2.

Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.

Thursday 6th December 1150

Far-red absorbing cationic phthalocyanine photosensitizers: Synthesis and evaluation of the photodynamic anti-cancer activity and the mode of cell death induction.

Novel zinc, magnesium and metal-free octasubstituted phthalocyanine photosensitizers bearing triethylammonioethylsulfanyl substituents in the peripheral or non-peripheral positions were synthesized and investigated for their photophysical properties (ΦΔ value up to 0.91,λmax up to 750 nm) and photodynamic anti-cancer activity. The photodynamic treatment of 3T3, HeLa, SK-MEL-28, and HCT 116 cancer cells revealed that the magnesium complexes were not active (IC50 〉100 μM), whereas the IC50 values of the...


Glycosylated Enfuvirtide: a Long-Lasting Glycopeptide with Potent Anti-HIV Activity.

Many peptide-based therapeutics have short circulatory half-lives. We report here that the pharmacokinetics of an anti-HIV peptide drug enfuvirtide (ENF) can be dramatically improved by a chemical glycosylation approach. A set of glycosylated ENFs with varying glycosylation sites and glycan structures were synthesized. Among these, a sialic acid-introduced peptide (SL-ENF) demonstrated a 15-fold extended half-life in rats relative to ENF (T1/2: 23.1 vs. 1.5 h), and its antiviral potency was comparable to th...


Stemistry: The Control of Stem Cells in Situ Using Chemistry.

A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and design of low molecular weight molecules that affect stem cells and thus have novel therapeutic activity. We believe that a successful agent from such a discover program would have profound ef...


Development of a series of aryl pyrimidine Kynurenine Monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic developm...

Saturday 21st November 1147

A Proof of Concept Study for Designed Multiple Ligands Targeting the Dopamine D2, Serotonin 5-HT2A and Muscarinic M1 Receptors.

Herein we describe the hybridization of a benzoxazinone M1 scaffold with D2 privileged structures derived from putative and clinically relevant antipsychotics to develop designed multiple ligands. The M1 mAChR is an attractive target for the cognitive deficits in key CNS disorders. Moreover, activity at D2 and 5-HT2A receptors has proven useful for antipsychotic efficacy. We identified 9 which retained functional activity at the target M1 mAChR and D2R and demonstrated high affinity for the 5-HT2AR.

Wednesday 17th June 1147

Structure-Activity Relationship for the Oxadiazole Class of Antibiotics.

The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-...


Design, Synthesis, and Characterization of Fatty Acid Derivatives of a Dimeric Peptide-Based Postsynaptic Density-95 (PSD-95) Inhibitor.

Dimeric peptide-based inhibitors of postsynaptic density-95 (PSD-95) can reduce ischemic brain damage and inflammatory pain in rodents. To modify the pharmacokinetic profile we designed a series of fatty acid linked dimeric ligands, which potently inhibits PSD-95 and shows improved in vitro blood plasma stability. Subcutaneous administration in rats showed extended stability and sustained release of these ligands. This can facilitate new pharmacological uses of PSD-95 inhibitors and further exploration of P...


Discovery and Development of Galeterone (TOK-001 or VN/124-1) for Treatment of all Stages of Prostate Cancer.

In our effort to discover potent and specific inhibitors of 17α-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes the biosynthesis of androgens from prenane precursors, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate which modulates multiple targets in the androgen receptor (AR) signaling pathway. This manuscript summarizes the mechanisms of action, scientific rationale, medicinal...

Friday 21st November 1146

Pachymodulin, a new functional formyl peptide receptor 2 (FPR2) peptidic ligand isolated from frog skin, has Janus-like immunomodulatory capacities.

Recruitment of leukocytes is essential in order to fight infections or to heal injuries; however excessive and/or prolonged responses favor the development of major inflammatory pathologies, such as cardiovascular or neurodegenerative diseases. Thus, it is of great interest to seek for novel compounds that can regulate leukocytes recruitment depending on the degree of inflammation. We have isolated and characterized by different chromatographic techniques, mass spectrometry and Edman sequencing a new hexape...

Saturday 26th July 1146

Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK).

The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of 44 as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo.

Friday 25th July 1146

Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease: Current Status and Future Trends.

Inhaled bronchodilators, including long-acting muscarinic receptor antagonists (LAMA) and long-acting beta2-adrenoreceptor agonists (LABA), are the mainstay of pharmacological treatment of stable chronic obstructive pulmonary disease (COPD). Among approved LAMA, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide, are administered once daily, whereas aclidinium bromide is administered every 12 hours. New LAMA are under development for COPD. Among the approved LABA, indacaterol has a 24-h dur...

Wednesday 30th April 1146

Simple Method Provides Resolution of Albumin, Lipoprotein, Free Fraction, and Chylomicron to Enhance the Utility of Protein Binding Assays.

Medicinal chemists have been encouraged in recent years to embrace high speed protein binding assays. These methods employ dialysis membranes in 96 well format or spin filters. Membrane-based methods do not separate lipoprotein binding from albumin binding and introduce interference despite membrane binding controls. Ultracentrifugation methods, in contrast, do not introduce interference if density gradients can be avoided and they resolve lipoprotein from albumin. A new generation of compact, fast ultracen...


Computational Methods for Medicinal Chemistry.

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