Abstract:
:Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kogan TP,Dupré B,Bui H,McAbee KL,Kassir JM,Scott IL,Hu X,Vanderslice P,Beck PJ,Dixon RAdoi
10.1021/jm9704917subject
Has Abstractpub_date
1998-03-26 00:00:00pages
1099-111issue
7eissn
0022-2623issn
1520-4804pii
jm9704917journal_volume
41pub_type
杂志文章abstract::Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01994
更新日期:2019-02-14 00:00:00
abstract::The cesium and tetramethylammonium (TMA) salts of polyoxotungstate anions with covalently attached organosilyl groups of formula [(RSi)2O]SiW11O39(4-), where R = CH2CH2COCH3, (CH2)3CN, and CH==CH2 (1-R, cesium salt, unless otherwise noted) have been prepared, purified, and spectroscopically characterized. The water so...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00085a008
更新日期:1992-04-03 00:00:00
abstract::New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis ( Mtb) inosine 5'-monophosphate dehydrogenase 2 ( MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guani...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01839
更新日期:2018-06-14 00:00:00
abstract::SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2, 2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2, 2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1-3 a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980438y
更新日期:1999-01-14 00:00:00
abstract::A series of novel cephalosporin compounds which have 3-[(aminopyrimidiniumyl)thio]methyl substituents was synthesized. They show high antimicrobial activity against various bacterial species including Pseudomonas aeruginosa. Structure-activity relationships with various thiopyrimidines, thiopyrimidiniums, bicyclic thi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00048a018
更新日期:1994-10-28 00:00:00
abstract::(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00195a010
更新日期:1979-09-01 00:00:00
abstract::2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyan...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00078a007
更新日期:1993-12-24 00:00:00
abstract::A series of analogues of streptonigrin, in which the quinoline of ring B is replaced by isoquinoline and the substituted pyridine of ring C is replaced by phenyl, nitrophenyl, aminophenyl, or benzyl functions, have been prepared. Thus, 1-substituted isoquinoline-5,8-diones with 7-amino or 6-(alkylamino) groups were pr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00110a018
更新日期:1991-06-01 00:00:00
abstract::A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00385a024
更新日期:1987-02-01 00:00:00
abstract::We present an RP-HPLC method, for the determination of logPoct values for neutral drugs, which combines ease of operation with high accuracy and which has been shown to work for a set of 36 molecules comprised largely of drugs. The general features of the method are as follows: (i) compound sparing (< or = 1 mL of a 3...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0000822
更新日期:2000-07-27 00:00:00
abstract::We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0302344
更新日期:2003-11-20 00:00:00
abstract::[4-Phenylalanine]oxytocin was prepared from Z-Cys(Bzl)-Tyr(Bzl)-Ile-Phe-Asn-Cys(Bzl)-Pro-Leu-Gly-NG2 (4) by deprotection with Na in NH3 followed by cyclization of the resulting disulfhydryl compound with ICH2CH2I. The protected peptide 4 was prepared from Boc-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwise solution metho...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00244a014
更新日期:1975-10-01 00:00:00
abstract::Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01473
更新日期:2021-01-14 00:00:00
abstract::A series of 2-guanidino-4-oxoimidazoline (deoxo-IZ) derivatives was prepared and showed potent antimalarial activities in rodent and Rhesus models. Compound 8e, the most potent analogues of this series, is the first non-8-aminoqinoline antimalarial that demonstrated radical curative activity in non-human primate by or...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200111g
更新日期:2011-07-14 00:00:00
abstract::A series of N,N-dialkyltryptamines with methylthio or methylenedioxy substituents in the 4, 5, and 6 positions and methyl or isopropyl on the side-chain nitrogen has been synthesized. The behavioral pharmacology of these compounds showed them to possess Bovet-Gatti profiles characteristic of hallucinogens, and the 5-m...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00350a005
更新日期:1982-08-01 00:00:00
abstract::This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% r...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00777
更新日期:2015-08-13 00:00:00
abstract::Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00076a008
更新日期:1993-11-26 00:00:00
abstract::Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing (1)H-(15)N heteronuclear single quantum coherence (HSQC) as well as one-dimensional (1)H and (19)F NMR to screen compound mix...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm201441k
更新日期:2012-01-26 00:00:00
abstract::Analogues of the antimycotic allylamine terbinafine were prepared in which the naphthalene and the tert-butyl-acetylene moieties were preserved, but the spacer between these two groups was varied, and the antifungal activity of the new compounds was evaluated. All modifications of the original spacer such as reduction...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00031a010
更新日期:1994-03-04 00:00:00
abstract::The accessible surface, described by Lee and Richards (the L&R surface: J. Mol. Biol. 1971, 55, 379), has remarkably useful properties for displaying ligand-protein interactions. The surface is placed one van der Waals radius plus one probe radius away from the protein atoms. The ligands are displayed in skeletal form...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00088a002
更新日期:1992-05-15 00:00:00
abstract::Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP val...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0614230
更新日期:2007-03-22 00:00:00
abstract::Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipoph...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301851v
更新日期:2013-03-28 00:00:00
abstract::A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010417v
更新日期:2002-02-14 00:00:00
abstract::Every week, articles disclosing new antifungal leads reported as promising starting points for optimization projects are published. In many cases, the mechanism that accounts for their antifungal activity has not been fully elucidated. More significantly, the detrimental impact that could result from certain embedded ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.5b00361
更新日期:2016-01-28 00:00:00
abstract::A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These res...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800970b
更新日期:2008-12-11 00:00:00
abstract::MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900809r
更新日期:2009-09-10 00:00:00
abstract::A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00211a004
更新日期:1977-01-01 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::Cancer cells generally generate higher amounts of reactive oxygen species than normal cells. On the basis of this difference, prodrugs have been developed (e.g., hydroxyferrocifen), which remain inactive in normal cells, but become activated in cancer cells. In this work we describe novel aminoferrocene-based prodrugs...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm2014937
更新日期:2012-01-26 00:00:00
abstract::The 2,3-bis[[(N-methylcarbamoyl)oxy]methyl]-3-pyrroline 1-oxide 5 was synthesized and tested in the murine P388 lymphocytic leukemia model. The compound showed significant reproducible activity and was more potent than indicine N-oxide. 1-Methyl-2-phenyl-3,4-bis[[(N-2- propylcarbamoyl)oxy]methyl]-3-pyrroline N-oxide (...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00394a036
更新日期:1987-11-01 00:00:00