Abstract：
:A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure-activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 microM of 5 m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Berger DM,Dutia M,Powell D,Floyd MB,Torres N,Mallon R,Wojciechowicz D,Kim S,Feldberg L,Collins K,Chaudhary Idoi
10.1016/j.bmc.2008.09.009subject
Has Abstractpub_date
2008-10-15 00:00:00pages
9202-11issue
20eissn
0968-0896issn
1464-3391pii
S0968-0896(08)00830-4journal_volume
16pub_type
杂志文章abstract：:7,8-Dihydroxy-3-methyl-isochromanone-4 (XJP), is a polyphenolic natural product with moderate antihypertensive activity. To obtain new agents with stronger potency and safer profile, we employed XJP and naftopidil as the lead compounds to design and synthesize a novel class of hybrids as antihypertensive agent candida...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2019.05.004
更新日期：2019-07-01 00:00:00
abstract：:The synthesis of new 1,4-bisalkylamino (2-4) and 1-alkylamino-4-chloro (5-6) substituted benzo[g]phthalazines is reported. Compounds 2-4 and 6 were prepared both in the free and heteroaromatic ring protonated forms. Bifunctional 6 contains the 1,4-bisaminopropylpiperazine chain as a linker between the two heteroaromat...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2010.05.053
更新日期：2010-07-15 00:00:00
abstract：:Inhibition of the isoforms of nitric oxide synthase (NOS) has important applications in therapy of several diseases, including cancer. Using 1400 W [N-(3-aminomethylbenzyl)acetamidine], thiocitrulline and N(delta)-(4,5-dihydrothiazol-2-yl)ornithine as lead compounds, series of N-benzyl- and N-phenyl-2-amino-4,5-dihydr...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0968-0896(03)00451-6
更新日期：2003-09-15 00:00:00
abstract：:C1027 is a potent antitumor agent that damages DNA. It has the unusual ability to produce double strand breaks and interstrand cross-links (ICLs) intracellularly, which enable it to initiate concurrent ataxia-telangiestasia mutated (ATM) and Rad-3 related (ATR) independent damage responses. The latter form of damage i...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2012.06.004
更新日期：2012-08-01 00:00:00
abstract：:The synthesis of new meridianin derivatives substituted at the C-5 position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. These compounds were tested for their kinase inhibitory potencies toward five kinases (CDK5/p25, CK1delta/epsilo...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2009.05.017
更新日期：2009-07-01 00:00:00
abstract：:Recent years have seen a resurgence in drug discovery efforts aimed at the identification of covalent inhibitors which has led to an explosion of literature reports in this area and most importantly new approved therapies. These reports and breakthroughs highlight the significant investments made across the industry i...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2020.115865
更新日期：2021-01-01 00:00:00
abstract：:Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used for Huisgen reacti...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2017.07.005
更新日期：2017-12-01 00:00:00
abstract：:A novel one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e]pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions. However, reaction of ketene amin...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0968-0896(01)00423-0
更新日期：2002-05-01 00:00:00
abstract：:REV1 protein is a mutagenic DNA damage tolerance (DDT) mediator and encodes two ubiquitin-binding motifs (i.e., UBM1 and UBM2) that are essential for the DDT function. REV1 interacts with K164-monoubiquitinated PCNA (UbPCNA) in cells upon DNA-damaging stress. By using AlphaScreen assays to detect inhibition of REV1 an...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2018.03.028
更新日期：2018-05-15 00:00:00
abstract：:In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [(3)H]dopamin...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2003.12.045
更新日期：2004-04-01 00:00:00
abstract：:Cyanocobalamin (vitamin B12) is an essential nutrient as well as a very useful carrier in drug delivery. Conjugates of vitamin B12 are investigated due to their wide range of therapeutic applications. We report the synthesis of six vitamin B12 conjugates, and the effect of conjugation on their solubilities and stabili...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2006.11.036
更新日期：2007-02-15 00:00:00
abstract：:In archaea the first general tetrapyrrole precursor 5-aminolevulinic acid (ALA) is formed via the tRNA-dependent five-carbon pathway from glutamate. We have cloned the hemA gene encoding the central enzyme of the pathway glutamyl-tRNA reductase from the methanogenic archaeon Methanobacterium thermoautotrophicum by com...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/0968-0896(96)00098-3
更新日期：1996-07-01 00:00:00
abstract：:Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396. ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2016.01.025
更新日期：2016-03-01 00:00:00
abstract：:Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2015.07.021
更新日期：2015-09-01 00:00:00
abstract：:The fungus Aspergillus japonicus MF275 produces himeic acid A (1), containing a 4-pyrone ring, along with its congeners, himeic acids B (2) and C (3). During culture, 1 was gradually converted to 3, the corresponding 4-pyridone derivative. A study of the relationship between the culture pH and the fungal metabolites s...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2018.02.034
更新日期：2018-05-01 00:00:00
abstract：:On the basis of a marine fungal phthalide (paecilocin A) skeleton, we synthesized 20 analogs and evaluated them for peroxisome proliferator-activated receptor gamma (PPAR-γ) binding and activation. Among these analogs, 6 and 7 had significant PPAR-γ binding activity, and 7 showed further PPAR-γ activation in rat liver...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2012.06.039
更新日期：2012-08-15 00:00:00
abstract：:The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ-calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2020.115433
更新日期：2020-05-01 00:00:00
abstract：:Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc enzymes acting as efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate. 16 different alpha-CA isoforms were isolated in mammals, where they play crucial physiological roles. Some of them are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), ot...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.bmc.2007.04.020
更新日期：2007-07-01 00:00:00
abstract：:Compound libraries comprise an integral component of drug discovery in the pharmaceutical and biotechnology industries. While in-house libraries often contain millions of molecules, this number pales in comparison to the accessible space of drug-like molecules. Therefore, care must be taken when adding new compounds t...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2012.03.037
更新日期：2012-09-15 00:00:00
abstract：:A facile preparation of 2-aminomethyl-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[3.3.1.1(1,7)]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2005.02.030
更新日期：2005-04-15 00:00:00
abstract：:Two new alpha-pyridone metabolites, iromycins E and F, were isolated from cultures of strain Streptomyces sp. Dra 17, thus expanding the recently discovered iromycin family. The inhibitory potential on the mitochondrial respiratory chain was examined and revealed that iromycin metabolites block NADH oxidation in beef ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2007.11.023
更新日期：2008-02-15 00:00:00
abstract：:Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy in biopharmaceutical drug development today. Although PEGylation has become a widely applied methodology to furnish therapeutic proteins and peptides with...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2017.09.016
更新日期：2018-06-01 00:00:00
abstract：:The signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells. Therefore, blocking the aberrant activity of STAT3 in tumor cells is a validated therapeutic strategy. To discover novel inhibitors of STAT3 activity, we screened against microbial natural products using a dual-...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2011.10.025
更新日期：2011-12-15 00:00:00
abstract：:The cellular penetration (CP) activity of functional molecules has attracted significant attention as one of the most promising new approaches for drug delivery. In particular, cell-penetrating peptides (CPPs) have been studied extensively in cellular engineering. Because there have been few large-scale systematic stu...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2013.02.030
更新日期：2013-05-01 00:00:00
abstract：:A facile and robust microwave-assisted solution phase parallel synthesis protocol was exercised for the development of a 38-member library of N,N'-disubstituted thiourea analogues (1-38) by using an identical set of conditions. The reaction time for synthesis of N,N'-disubstituted thiourea analogues was drastically re...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2016.07.042
更新日期：2016-09-15 00:00:00
abstract：:This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 wa...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2011.05.057
更新日期：2011-07-15 00:00:00
abstract：:To aid the pharmaceutical and cosmetic industry in the development of alternatives to prevent melanin-related hyperpigmentation disorders, the plant Dalea elegans was submitted to fractionation with the aim of obtaining its anti-tyrosinase principle. Bioguided fractionation of D. elegans led to the isolation of 5,2',4...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2011.04.025
更新日期：2011-06-01 00:00:00
abstract：:In recent years, special attention has been paid to the A3 adenosine receptor (A3AR) as a possible pharmacological target to treat intestinal inflammation. In this work, it was set up a novel method to quantify the concentration of a promising anti-inflammatory agent inside and outside of intestinal barrier using the ...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2019.06.011
更新日期：2019-08-01 00:00:00
abstract：:Elucidating the mechanism of action of bioactive compounds, such as commonly used pharmaceutical drugs and biologically active natural products, in the cells and the living body is important in drug discovery research. To this end, isolation and identification of target protein(s) for the bioactive compound are essent...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2011.12.022
更新日期：2012-03-15 00:00:00
abstract：:We report a chiral switch in the configuration of 1-(p-methoxyphenyl)-propan-2-ol, synthesized in aqueous media by ketoreductase in the presence of high concentration of gamma-CD. NMR, ECD and fluorescence spectrometry were used in the effort to explain this unexpected effect. A comparison has been made between the ca...
journal_title：Bioorganic & medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.bmc.2010.07.070
更新日期：2010-09-15 00:00:00
