Abstract：
:Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported antituberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 microM and 2.6 microM against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d an interesting lead compound. A number of modifications were made to the structure of 9d, and a series of active compounds were discovered. Although some neurotoxicity was observed at a high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Mao J,Yuan H,Wang Y,Wan B,Pieroni M,Huang Q,van Breemen RB,Kozikowski AP,Franzblau SGdoi
10.1021/jm900340asubject
Has Abstractpub_date
2009-11-26 00:00:00pages
6966-78issue
22eissn
0022-2623issn
1520-4804journal_volume
52pub_type
杂志文章abstract：:2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01835
更新日期：2020-05-14 00:00:00
abstract：:Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800149m
更新日期：2008-10-23 00:00:00
abstract：:The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201416p
更新日期：2012-05-24 00:00:00
abstract：:Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100478y
更新日期：2010-08-12 00:00:00
abstract：:The concept of molecular hybridization led us to discover a novel series of coumarin-dihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301281e
更新日期：2013-01-10 00:00:00
abstract：:In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980656r
更新日期：1999-04-22 00:00:00
abstract：:Novel analogues of the class III antiarrhythmic agent 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, 1 (CK-1649), were prepared and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00395a021
更新日期：1987-12-01 00:00:00
abstract：:A method for preparing a variety of 7-alkyl-6,7- didehydromorphinans from the corresponding 6- morphinanones is described. The key intermediates in this sequence are the 7-formyl derivatives. The two epimeric B/C-trans-7-(1- hydroxypentyl ) morphinans ( 16a ,b) are stereochemically similar to the endo- ethanotetrahydr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00371a013
更新日期：1984-05-01 00:00:00
abstract：:Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI ri...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.0c00524
更新日期：2020-10-22 00:00:00
abstract：:Here, we report the synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu/kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as those the two reference c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0605785
更新日期：2006-09-07 00:00:00
abstract：:A computational methodology is introduced to systematically organize compound analogue series according to substitution sites and identify combinations of sites that determine structure-activity relationships (SARs) and make large contributions to SAR discontinuity. These sites are prime targets for further chemical m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900107b
更新日期：2009-05-28 00:00:00
abstract：:The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0498102
更新日期：2004-07-29 00:00:00
abstract：:Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492094
更新日期：2005-05-05 00:00:00
abstract：:A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 AR, which had bee...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701159t
更新日期：2008-03-27 00:00:00
abstract：:Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00104a017
更新日期：1992-12-25 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：:Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-base...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00077
更新日期：2020-09-10 00:00:00
abstract：:We report analogues of N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Ilys-Pro-D-Ala- NH2, the parent antagonist (PA), which is a potent antagonist of LHRH. To simplify future radioactive labeling we prepared N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Lys(Pic)-Leu-Arg-Pro-D-Ala-NH2 (4), [Arg8]PA, which had good activit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00082a004
更新日期：1992-02-21 00:00:00
abstract：:The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00040a004
更新日期：1994-07-08 00:00:00
abstract：:Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetam...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00783
更新日期：2018-09-13 00:00:00
abstract：:Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0309452
更新日期：2004-02-12 00:00:00
abstract：:n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00371a009
更新日期：1984-05-01 00:00:00
abstract：:Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a019
更新日期：1980-01-01 00:00:00
abstract：:Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Prev...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200764t
更新日期：2011-08-25 00:00:00
abstract：:4-(Dimethylamino)- and 4-(methylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives were prepared as analogues of previously reported 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Metalation of benzanilide with n-butyllithium, addition of 4-(dimethylamino)cyclohexanone, and acidification afforded a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a025
更新日期：1981-05-01 00:00:00
abstract：:Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0601001
更新日期：2006-06-29 00:00:00
abstract：:Methodology is presented for assembling fluorescently labeled bivalent molecules from monovalent constituents, without side chain protection or coupling agents. To illustrate the procedure, a series of bivalent peptidomimetics directed toward the Trk receptors were prepared and screened via fluorescent activated cell ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm034103e
更新日期：2003-08-14 00:00:00
abstract：:A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a021
更新日期：1990-02-01 00:00:00
abstract：:The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3014597
更新日期：2013-03-14 00:00:00
abstract：:The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0308038
更新日期：2003-07-31 00:00:00
