Abstract：
:A series of methylated analogues of 6-hydroxydopamine (6-OHDA) has been synthesized and evaluated as irreversible inhibitors of catechol O-methyltransferase (COMT). These analogues have been prepared in an effort to elucidate the mechanism involved in the inactivation of this enzyme by 6-OHDA. The analogues prepared had methyl groups incorporated in the 2 and/or 5 positions of 6-OHDA so as to block nucleophilic attakc at these positions in the corresponding oxidation products [6-hydroxydopamine-p-quinone (6-OHDAQ), aminochromes I and II]. Such 2- and/or 5-methylated 6-OHDA analogues were found to be inhibitors of COMT with the inactivation apparently resulting from modification of an essential amino acid residue at the active site of the enzyme. The activity of these analogues as inhibitors of COMT argues against a mechanism involving a 1,4 Michael addition reaction by a protein nucleophile at the 2 or 5 positions on 6-OHDAQ or on the corresponding aminochromes. Instead, an alternative mechanism is proposed to explain these data, which involves attack of a protein nucleophile at the carbonyl group in the 6 position of 6-OHDAQ or at the imine functionality on aminochromes I and II. The results of the present experiments have provided insight into the mechanism involved in inactivation of COMT by 6-OHDA. In addition, this study has provided considerable insight into the chemical reactivity of the electrophilic species generated after oxidation of 6-OHDA.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Borchardt RT,Reid JR,Thakker DRdoi
10.1021/jm00232a007subject
Has Abstractpub_date
1976-10-01 00:00:00pages
1201-9issue
10eissn
0022-2623issn
1520-4804journal_volume
19pub_type
杂志文章abstract：:The synthesis and structure-activity relationships of a new class of vinylcephalosporins substituted with a lactamyl residue are described. These compounds show excellent activity against enterococci and retain the broad spectrum activity of third-generation cephalosporins such as ceftriaxone. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950886v
更新日期：1996-04-26 00:00:00
abstract：:Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049861z
更新日期：2004-08-26 00:00:00
abstract：:Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identif...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101499u
更新日期：2011-04-14 00:00:00
abstract：:A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00003a010
更新日期：1995-02-03 00:00:00
abstract：:Cysteine proteases play an important role in cell migration and tumor metastasis. Therefore, their inhibitors are of colossal interest, having potential to be developed as effective antimetastatic drugs for tumor chemotherapy. Traditionally, secondary metabolites from streptomyces show a wide range of diversity with r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9014179
更新日期：2010-07-22 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：:2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00067a015
更新日期：1993-07-23 00:00:00
abstract：:Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00184a002
更新日期：1980-10-01 00:00:00
abstract：:New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00760
更新日期：2016-07-14 00:00:00
abstract：:Because of the double-edged nature of NO, the development of isoform-selective NOS substrates is a highly desirable goal. Given the striking similarity in the heme active sites of the three NOS isoforms, it presents an challenging problem. Several N-aryl-N'-hydroxyguanidines have recently been shown as substrates that...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0340703
更新日期：2003-06-05 00:00:00
abstract：:Cell division cycle 25 (Cdc25) proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent attractive drug targets for anticancer therapies. To discover more potent and diverse inhibitors of Cdc25 biological activity, virtual screening was performed by docking 2.1 m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201624h
更新日期：2012-05-10 00:00:00
abstract：:The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous adm...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00119a015
更新日期：1988-11-01 00:00:00
abstract：:Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1012006
更新日期：2011-01-13 00:00:00
abstract：:The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01128
更新日期：2020-10-08 00:00:00
abstract：:An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800545k
更新日期：2008-09-25 00:00:00
abstract：:Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01644
更新日期：2016-04-14 00:00:00
abstract：:It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of [3H]-3 beta-(4-fluorophenyl)tro...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00059a010
更新日期：1993-04-02 00:00:00
abstract：:Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DH...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0203534
更新日期：2003-02-13 00:00:00
abstract：:Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00368a021
更新日期：1984-02-01 00:00:00
abstract：:Two new peptides, tailored after Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (TRI), namely, Ac-Thr-D-Trp(CHO)-Phe-NMe alpha MeBzl (TRA) and Ac-Thr-D-Trp(CHO)-Oic-NMeBzl (TOI), in which Phe is replaced by (3aS, 7aS)-octahydroindole-2-carboxylic acid, proved more potent and selective NK1 antagonists. The conformational properties of a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960213s
更新日期：1997-02-14 00:00:00
abstract：:As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980223o
更新日期：1999-03-11 00:00:00
abstract：:In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72,107), a series of 5-[4-(2- or 4-azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabeti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00092a012
更新日期：1992-07-10 00:00:00
abstract：:Two complete and two partial structure-activity relationship scans of the active fragment of human growth hormone-releasing hormone, [Nle27]-hGHRH(1-29)-NH2, have identified potent agonists in vitro. Single-point replacement of each amino acid by alanine led to the identification of [Ala8]-, [Ala9]-, [Ala15]- (Felix e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970618s
更新日期：1998-02-26 00:00:00
abstract：:A series of novel (1,3-dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones was synthesized. Pharmacological evaluation of these compounds demonstrated central nervous system depressant activity, potential anticonvulsant properties, and a low order of acute toxicity. In addition, selected compounds showed potential antipsyc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00377a003
更新日期：1984-11-01 00:00:00
abstract：:Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs diffe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00996
更新日期：2017-09-28 00:00:00
abstract：:The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00743
更新日期：2018-09-13 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：:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00845
更新日期：2017-11-09 00:00:00
abstract：:Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a045
更新日期：1990-02-01 00:00:00
abstract：:A variety of derivatives of 2-pyridinecarboxaldehyde 1-oxide benzenesulfonylhydrazone, containing substituents on the benzene or pyridine rings as well as on the nitrogen atom which is bonded directly to the sulfonyl group, have been synthesized. The antineoplastic activity of these compounds has been assessed in mice...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00180a010
更新日期：1980-06-01 00:00:00
