Abstract：
:SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other cancer types. Recently SHP-2 became a new drug target, but till now little has been done in this field. In the present study, 17 2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2 inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation stabilize enzyme-inhibitor complex.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Geronikaki A,Eleftheriou P,Vicini P,Alam I,Dixit A,Saxena AKdoi
10.1021/jm8004306subject
Has Abstractpub_date
2008-09-11 00:00:00pages
5221-8issue
17eissn
0022-2623issn
1520-4804journal_volume
51pub_type
杂志文章abstract：:The photo "Wolff" rearrangement of readily available 2-diazoceph-3-em oxides (1) directly affords carbapen-2-ems, allowing a facile entry into a ring system previously accessible only by total synthesis, lengthly semisynthesis or fermentation. The chirality of the cephalosporin is accurately translated into the corres...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a048
更新日期：1990-01-01 00:00:00
abstract：:HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400164c
更新日期：2014-03-13 00:00:00
abstract：:Doxazolidine (doxaz) is a new anthracycline anticancer agent. While structurally similar to doxorubicin (dox), doxaz acts via a distinct mechanism to selectively enhance anticancer activity over cardiotoxicity, the most significant clinical impediment to successful anthracycline treatment. Here, we describe the synthe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300714p
更新日期：2012-07-26 00:00:00
abstract：:The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these compl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00151a023
更新日期：1986-01-01 00:00:00
abstract：:A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00122a034
更新日期：1989-02-01 00:00:00
abstract：:A series of substituted 3-aryl- and hydroxy-3-aryloctahydropyrido[2,1-c][1,4]oxazines has been synthesized for purposes of investigating potentially useful CNS pharmacological actions of this novel heterocyclic system. The preferred conformation of the bicyclic system of the parent compounds, 1 and 2, has been shown t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00203a010
更新日期：1978-05-01 00:00:00
abstract：:Several known alpha-amino acid analogues and a new compound, N-chloroacetylphosphoramidate, a carbamyl phosphate analogue, were screened as antitumor agents. All gave 50% growth inhibition of cultures of human epidemeroid carcinoma of the nasopharynx at dosage levels of 2-8 mug/ml while showing no activity against L12...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a026
更新日期：1977-03-01 00:00:00
abstract：:Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101101q
更新日期：2010-12-23 00:00:00
abstract：:To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0304562
更新日期：2004-01-15 00:00:00
abstract：:2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We iden...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061045z
更新日期：2007-01-11 00:00:00
abstract：:Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds. In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00186a014
更新日期：1980-12-01 00:00:00
abstract：:A series of cis- and trans-dihydroxycotahydrobenzo[f]quinoline congeners of dopamine has been prepared, in which the N substitutent is H, ethyl, or n-propyl. The trans isomers include the dopamine moiety held rigidly in an antiperiplanar diposition which is believed to be necessary for certian central and peripheral d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00190a002
更新日期：1979-04-01 00:00:00
abstract：:We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200536d
更新日期：2011-08-25 00:00:00
abstract：:The high secretion rate of 18-hydroxydeoxycorticosterone in hypertensives and the steroids implication as a mineralocorticoid has led to the synthesis of potential di-, tetra-, and hexahydro metabolites of it and 18-hydroxy-progesterone. These potential metabolites have been synthesized by reduction of the double bond...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a014
更新日期：1985-02-01 00:00:00
abstract：:Several substance P analogues containing various D-amino acid modifications have been synthesized by the solid-phase procedure, detached from the solid support by ammonolysis, and purified by gel filtration combined with reversed-phase chromatography. Three compounds were fair to very potent competitive antagonists of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00353a008
更新日期：1982-11-01 00:00:00
abstract：:The recent discovery that the formaldehyde conjugates of doxorubicin and daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast cancer cells prompted the search for hydrolytically more stable anthracycline-formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the parent dru...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970739s
更新日期：1998-04-09 00:00:00
abstract：:The synthesis of two new series of dicarboxylic acid dipeptides and two sulfhydryl-containing inhibitors are described. The in vitro enkephalinase inhibition data and some in vivo analgesic data are presented for these compounds. For the dibenzylglutaric acid series structure-activity relationships and in vivo analges...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00132a005
更新日期：1989-12-01 00:00:00
abstract：:Two compounds, analogues of cephalexin with 2- and 4-pyridone groups at C-3, were prepared. Biological evaluation found the compounds to exhibit activity against Gram-positive and Gram-negative organisms in vitro and in vivo. The compounds were only active in vivo on subcutaneous administration. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00197a026
更新日期：1979-11-01 00:00:00
abstract：:Computational ADME (absorption, distribution, metabolism, and excretion) models may be used early in the drug discovery process in order to flag drug candidates with potentially problematic ADME profiles. We report the development, validation, and application of quantitative structure-property relationship (QSPR) mode...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020491t
更新日期：2003-07-03 00:00:00
abstract：:A molecular model of the human A(2B) adenosine receptor containing seven transmembrane alpha helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A(2B) receptor was performed, and the diffe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049418o
更新日期：2005-11-03 00:00:00
abstract：:In this paper we report the systematic search for new, potent, and selective DPP II inhibitors. A study of the structure-activity relationship was conducted starting from aminoacyl pyrrolidides as lead compounds. Rational exploration of the P(1) and P(2) building blocks led to the discovery of some very potent DPP II ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0308803
更新日期：2003-11-06 00:00:00
abstract：:A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 differe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00564
更新日期：2020-07-23 00:00:00
abstract：:A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a020
更新日期：1985-02-01 00:00:00
abstract：:The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIA...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400732v
更新日期：2013-10-24 00:00:00
abstract：:A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030498q
更新日期：2004-03-11 00:00:00
abstract：:A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this comp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980077m
更新日期：1998-07-02 00:00:00
abstract：:Results from previous studies indicate that rabbit liver microsomal cytochrome P-450 catalyzes the C-5' two-electron oxidation of (S)-nicotine stereoselectivity with preferential loss of the pro-(E)-hydrogen atom trans to the pyridine ring. We now have examined the regio- and stereochemical features of the oxidation o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00398a024
更新日期：1988-03-01 00:00:00
abstract：:The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01379
更新日期：2017-02-23 00:00:00
abstract：:Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog of dasatinib, a multitargeted kinase inhibitor, are reported. Com...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070342g
更新日期：2007-11-15 00:00:00
abstract：:A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, al...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960070+
更新日期：1996-09-13 00:00:00
