Abstract：
:A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kelley JL,Bullock RM,Krochmal MP,McLean EW,Linn JA,Durcan MJ,Cooper BRdoi
10.1021/jm960662ssubject
Has Abstractpub_date
1997-09-26 00:00:00pages
3207-16issue
20eissn
0022-2623issn
1520-4804pii
jm960662sjournal_volume
40pub_type
杂志文章abstract：:Synthetic routes were developed to access a variety of novel 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-one analogs which were evaluated as 5-lipoxygenase (5-LO) inhibitors. The parent structure, 1-phenylperhydro-1,2,4-triazin-3-one (4), was found to be a selective inhibitor of 5-LO in broken cell, intact cell, and human...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960372b
更新日期：1996-09-27 00:00:00
abstract：:Monoamine oxidase (MAO) exists in two forms distinguishable by substrate specificity. Inhibition of MAO A is believed to be responsible for the antidepressant activity of MAO inhibitors. A group of N-arylacetamides are highly specific inhibitors of MAO A, some with IC50 values in the 10-100 nM range. The requirements ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00039a021
更新日期：1994-06-24 00:00:00
abstract：:Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00746
更新日期：2015-09-10 00:00:00
abstract：:The synthesis of the first 4-amino-3-carboxy-beta-carboline derivative (35) is described. This synthesis is based on ozonolysis of the 4-vinyl-beta-carboline-3-carboxamide 17 to give the 4-aldehyde 20 and potassium permanganate oxidation of the latter to the 4-carboxylic acid 34 followed by a DPPA-promoted Curtius rea...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00001a024
更新日期：1995-01-06 00:00:00
abstract：:An extension of the Mannich reaction, in which aminomethylation of the five position of uracil, is reported. Thus, primary and secondary alkylamines and primary aromatic amines containing ring-activating groups led to the title compounds 3-10. Compound 11 in which the aromatic ring contains the ring-deactivating nitro...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00224a032
更新日期：1976-02-01 00:00:00
abstract：:The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase,...
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pub_type： 杂志文章
doi：10.1021/jm0009639
更新日期：2000-10-19 00:00:00
abstract：:Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resist...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00347
更新日期：2020-07-23 00:00:00
abstract：:Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhib...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301818g
更新日期：2013-04-25 00:00:00
abstract：:Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00176a011
更新日期：1980-02-01 00:00:00
abstract：:The present study describes a novel in vitro platform for physicochemical profiling of compounds, based on their impact on the air/water interfacial tension. Interfacial partitioning coefficient, cross-sectional area, and critical micelle concentration were derived from the Gibbs adsorption isotherms recorded for 76 s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0309001
更新日期：2004-03-25 00:00:00
abstract：:Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0301787
更新日期：2003-10-23 00:00:00
abstract：:Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the do...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801575w
更新日期：2009-04-09 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：:The Mediterranean tunicate Stolonica socialis contains a new class of powerful cytotoxic acetogenins, generically named stolonoxides. In this paper, which also details the isolation and chemical characterization of a minor component (3a) of the tunicate extract, we report the potent inhibitory activity (IC(50) < 1 mic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0011373
更新日期：2001-07-05 00:00:00
abstract：:Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2-alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950876u
更新日期：1996-06-21 00:00:00
abstract：:Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a013
更新日期：1984-09-01 00:00:00
abstract：:We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmaco...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020171+
更新日期：2002-11-21 00:00:00
abstract：:The 5'-phosphate (1) of the antiviral nucleoside 5-cyano-2'-deoxyuridine was synthesized and evaluated for inhibition of thymidylate synthetase purified from methotrexate-resistant Lactobacillus casei. Compound 1 was a potent competitive inhibitor with a K1 of 0.55 microns. Irreversible enzyme inhibition by this compo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00195a028
更新日期：1979-09-01 00:00:00
abstract：:Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970690q
更新日期：1998-10-22 00:00:00
abstract：:Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01682
更新日期：2019-02-28 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00093a009
更新日期：1992-07-24 00:00:00
abstract：:On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, whic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0603466
更新日期：2006-10-05 00:00:00
abstract：:The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generate...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm700966p
更新日期：2008-04-10 00:00:00
abstract：:The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00081a021
更新日期：1992-02-07 00:00:00
abstract：:Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previous...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5011868
更新日期：2015-01-08 00:00:00
abstract：:We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030502y
更新日期：2004-12-30 00:00:00
abstract：:Ligand-induced stabilization of G-quadruplex structures formed by the human telomeric DNA is an active area of research. The compounds which stabilize the G-quadruplexes often lead to telomerase inhibition. Herein we present the results of interaction of new monomeric and dimeric ligands having 1,3-phenylene-bis(piper...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200860b
更新日期：2012-04-12 00:00:00
abstract：:Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crys...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01060
更新日期：2020-02-27 00:00:00
abstract：:Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. H...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020536q
更新日期：2003-04-10 00:00:00
abstract：:The coordination complex cyclo-tetrakis[bis(1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato++ +)mu-o xotitanium(IV)] has been synthesized and characterized with IR and NMR spectroscopies and X-ray diffraction. The core of this species consists of an eight-membered Ti-mu-oxo ring with alternate short-long Ti-O bond lengths....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990539b
更新日期：2000-10-05 00:00:00
