Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.
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PMID:Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. 1037 23

A wheat line, Bai Nong 3217 x Mardler BC5F4 with resistance to powdery mildew was used in the study. A suppression subtractive hybridization cDNA library was constructed from wheat leaves challenged by Erysiphe graminis DC at primary stage. Seven hundred and sixty ESTs were acquired, and the ESTs similarity analysis based on BLASTx software was finished by comparing sequences in nr database of GenBank. Two hundred and seventy one ESTs' functions were identified in the total ESTs. The results showed that GTP-binding proteins associated signal pathway, salicylic acid pathway, MAP pathway etc were supposed to involved in the disease resistance reaction. SAR genes were rich not only in varieties but also in quantity, including five kinds of phyogenesis-related proteins, induced defence-resistance genes, heat shock proteins and genes induced by abiotic-stresses etc. There are lots of evidence to testify PAL pathway, cell wall modification, cell survive system serving in the disease resistance. In the function unknown ESTs, many homologous ESTs were found from other biotic and abiotic-stresses selected cDNA libraries after BLASTn analysis, the stresses included pathogen, salt, drought, cold, high temperature etc. The novel ESTs was 16.6% in total ESTs.
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PMID:[ESTs analysis of resistance to powdery mildew in wheat at primary infected stage]. 1209 31

The p38 MAP kinases are a family of serine/threonine protein kinases that play a key role in cellular pathways leading to pro-inflammatory responses. We have developed and implemented a method for rapidly identifying and optimizing potent and selective p38alpha inhibitors, which is amenable to other targets and target classes. A diverse library of druggable, purified and quantitated molecules was assembled and standardized enzymatic assays were performed in a microfluidic format that provided very accurate and precise inhibition data allowing for development of SAR directly from the primary HTS. All compounds were screened against a collection of more than 60 enzymes (kinases, proteases and phosphatases), allowing for removal of promiscuous and non-selective inhibitors very early in the discovery process. Follow-up enzymological studies included measurement of concentration of compound in buffer, yielding accurate determination of K(i) and IC50 values, as well as mechanism of action. In addition, active compounds were screened against less desirable properties such as inhibition of the enzyme activity by aggregation, irreversible binding, and time-dependence. Screening of an 88,634-compound library through the above-described process led to the rapid identification of multiple scaffolds (>5 active compounds per scaffold) of potential drug leads for p38alpha that are highly selective against all other enzymes tested, including the three other p38 isoforms. Potency and selectivity data allowed prioritization of the identified scaffolds for optimization. Herein we present results around our 3-thio-1,2,4-triazole lead series of p38- selective inhibitors, including identification, SAR, synthesis, selectivity profile, enzymatic and cellular data in their progression towards drug candidates.
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PMID:Discovery of highly selective inhibitors of p38alpha. 1617 39

In this paper, a new despeckling method based on undecimated wavelet decomposition and maximum a posteriori MIAP) estimation is proposed. Such a method relies on the assumption that the probability density function (pdf) of each wavelet coefficient is generalized Gaussian (GG). The major novelty of the proposed approach is that the parameters of the GG pdf are taken to be space-varying within each wavelet frame. Thus, they may be adjusted to spatial image context, not only to scale and orientation. Since the MAP equation to be solved is a function of the parameters of the assumed pdf model, the variance and shape factor of the GG function are derived from the theoretical moments, which depend on the moments and joint moments of the observed noisy signal and on the statistics of speckle. The solution of the MAP equation yields the MAP estimate of the wavelet coefficients of the noise-free image. The restored SAR image is synthesized from such coefficients. Experimental results, carried out on both synthetic speckled images and true SAR images, demonstrate that MAP filtering can be successfully applied to SAR images represented in the shift-invariant wavelet domain, without resorting to a logarithmic transformation.
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PMID:Multiresolution MAP despeckling of SAR images based on locally adaptive generalized Gaussian pdf modeling. 1707 98

High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.
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PMID:Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. 1763 46

Efforts to synthesize potential methionine aminopeptidase inhibitors is described. Preliminary SAR and docking studies served as a guide to design the compound libraries. "Chromatography-free" synthesis of various heterocyclic amides was realized by using a high-load, soluble coupling reagent derived via ring-opening metathesis polymerization (ROMP). Subsequent microwave-assisted Suzuki reactions with ortho-substituted arylboronic acids, followed by chromatographic purification afforded a 55-member library in high yields and purities. While the biological testing was not satisfactory, concurrent X-ray crystallography studies revealed key structural features essential for inhibition of methionine aminopeptidase, which directed fruitful results reported in the accompanying manuscript. In addition, in silico Lipinksi profiles and ADME properties of the library are also reported.
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PMID:Studies towards the synthesis of methionine aminopeptidase inhibitors: diversification utilizing a ROMP-derived coupling reagent. 1816 94

Development of an ionic immobilization, diversification, and release method for the generation of methionine aminopeptidase inhibitors is reported. This method involves the immobilization of 5-bromofuran-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid onto PS-BEMP, followed by Suzuki reaction on a resin-bound intermediate and subsequent release to provide products in moderate yields and excellent purities. Compound potencies were evaluated on the Co(II), Mn(II), Ni(II), and Fe(II) forms of Escherichia coli MetAP1. The furoic-acid analogs were found to be Mn(II) selective with IC 50 values in the low micromolar range. Qualitative SAR analysis, supplemented by molecular modeling studies, provides valuable information on structural elements responsible for potency and selectivity.
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PMID:Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors. 1816 95

f152A1 was isolated from a fermentation broth of Curvularia verruculosa and characterized as a potent inhibitor of TNFalpha transcription, with anti-inflammatory activity. f152A1 and several analogues displayed inhibitory activity against the MAP kinases ERK2 and MEK1 in in vitro kinase assays. Through SAR studies on f152A1 and analogues prepared via total synthesis, we have identified structural features that contribute to inhibitory activity. To rationalize these results and to aid in the discovery process, a combination of high temperature molecular dynamics and MOPAC AM1 semiempirical molecular orbital method studies was used in studies that yielded a postulated active conformation, M1(8). This active conformation M1(8) reflects a high degree of conformational similarity among f152A1 and its more potent analogues. In view of the highly reactive cis-enone moiety in the flexible 14-membered resorcylic acid lactone ring of f152A1, the chemical reactivities of the enone moieties in various analogues were assessed by molecular orbital calculations. The enone reactivity analyses suggested that these inhibitors were prone to Michael addition at the alpha,beta-unsaturated ketone moiety and might chemically react with cysteine residues in the ATP-binding site of MAP kinases. Reactivity of the cis-enone moiety and the M1(8) conformation make important contributions to the inhibitory activity of MAP kinases.
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PMID:Conformational analyses and MO studies of f152A1 and its analogues as potent protein kinase inhibitors. 1999 92

The introduction of multi-agent chemotherapy dramatically improved the outcome for patients with osteosarcoma. However, we appear to have reached a plateau in outcome with a long-term event-free survival of 60-70%. Therefore, detection of further improvements will likely require larger numbers of patients. This goal is best achieved via randomized clinical trials (RCTs) requiring large-scale cooperation and collaboration. With this background, four multinational groups agreed on the merits of collaboration: Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG); they designed a study to determine whether altering postoperative therapy based on histological response improved the outcome. The study design includes a backbone of 10 weeks of preoperative therapy using MAP (methotrexate, Adriamycin and cisplatin). Following surgery, patients are stratified according to histological response. Patients classified as "good responders" (>or=90% necrosis) are randomized to continue MAP or to receive MAP followed by maintenance pegylated interferon, while "poor responders" (<90% necrosis) are randomized to either continue MAP or to receive MAPIE (MAP+ifosfamide, etoposide). The design includes the registration of 1,400 patients over 4 years as well as the evaluation of quality of life using two different instruments. The group has established an efficient infrastructure to ensure successful implementation of the trial. This has included the EURAMOS Intergroup Safety Desk, which has established an international system for SAE, SAR and SUSAR reporting to the relevant competent authorities and ethics committees for each participating country. The group has also developed trial site monitoring and data center audits with funding from the European Science Foundation (ESF). The ESF has also funded three training courses to familiarize institutional staff with the requirements of multinational GCP trials. We have established a successful collaboration, and as of February 2008, 901 patients have been enrolled (COG 448; COSS 226; EOI 181; SSG 46) from 249 institutions in 16 different countries. As expected, 80% of the patients are <18 years of age, and accrual into the Quality of Life sub-study is proceeding as planned with 90% of the subjects agreeing to participate. International awareness is increasing and procedures for applicant countries wishing to join the collaboration have been implemented. Details about EURAMOS can be found at www.euramos.org. International trials in rare diseases are practicable with appropriate funding, planning and support. Although the implementation of such trials is difficult and time consuming, it is a worthwhile effort to rapidly complete RCTs and identify interventions that will improve the outcome of all osteosarcoma patients.EURAMOS-1 is the fastest accruing osteosarcoma trial and is already the largest osteosarcoma study conducted.
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PMID:International collaboration is feasible in trials for rare conditions: the EURAMOS experience. 2021