Abstract：
:Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lin J,Deng H,Jin L,Pandey P,Quinn J,Cantin S,Rynkiewicz MJ,Gorga JC,Bibbins F,Celatka CA,Nagafuji P,Bannister TD,Meyers HV,Babine RE,Hayward NJ,Weaver D,Benjamin H,Stassen F,Abdel-Meguid SS,Strickler JEdoi
10.1021/jm060978ssubject
Has Abstractpub_date
2006-12-28 00:00:00pages
7781-91issue
26eissn
0022-2623issn
1520-4804journal_volume
49pub_type
杂志文章abstract：:Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060491j
更新日期：2006-10-19 00:00:00
abstract：:The synthesis of a series of 1-phenoxy-3-[[(substituted-amido)alkyl]amino]-2-propanols is described. Many of the compounds are more potent than propanolol as beta blockers, while having cardioselectivity comparable to that of practolol, when given intravenously to anesthetized cats. The structure-activity relationship...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00353a004
更新日期：1982-11-01 00:00:00
abstract：:Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0707166
更新日期：2007-11-15 00:00:00
abstract：:A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00703
更新日期：2016-09-08 00:00:00
abstract：:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00443
更新日期：2017-08-24 00:00:00
abstract：:The design and synthesis of 3-amino-2-oxo-4-phenylbutanoic acid amides (alpha-keto amides), a new class of aminopeptidase inhibitor, are described. These compounds, illustrated by the Phe-Leu analogue 2, are effective inhibitors of arginyl aminopeptidase (Ki = 1.5 microM), cytosol aminopeptidase (Ki = 1.0 microM), and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00081a005
更新日期：1992-02-07 00:00:00
abstract：:The synthesis of two new nucleotide analogues is described. 5'-Sulfamino-5'-deoxyadenosine (1) was prepared by reaction of 5'-amino-5'-deoxyadenosine with (CH3)3N.203, and 5'-sulfamino-5'-deoxythymidine (2) was prepared from 5'-amino-5'-deoxythymidine by a similar reaction. The 5'-sulfamino nucleosides are shown to be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00205a024
更新日期：1978-07-01 00:00:00
abstract：:A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineopla...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000045a
更新日期：2000-07-13 00:00:00
abstract：:(+)-Deoxoartelinic acid (13), a new hydrolytically stable, water-soluble, and potent non-acetal-type antimalarial drug candidate, was successfully prepared from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. This compound showed superior in vitro antimalarial activity against t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020244p
更新日期：2002-10-24 00:00:00
abstract：:Isoform-selective antagonists of the lysophosphatidic acid (LPA) G-protein coupled receptors (GPCRs) have important potential uses in cell biology and clinical applications. Novel phosphonothioate and fluoromethylene phosphonate analogues of carbacyclic phosphatidic acid (ccPA) were prepared by chemical synthesis. The...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060351+
更新日期：2006-08-24 00:00:00
abstract：:A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960092w
更新日期：1996-07-05 00:00:00
abstract：:A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based sub...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9802158
更新日期：1998-08-27 00:00:00
abstract：:This paper describes the synthesis and biological evaluation of a new class of peptidomimetic falcipain-2 inhibitors based on a 1,4-benzodiazepine scaffold combined with various alpha,beta-unsaturated electrophilic functions such as vinyl-ketone, -amide, -ester, and -nitrile. The profile of reactivity of this class of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900047j
更新日期：2009-04-09 00:00:00
abstract：:If no structural information about a particular target protein is available, methods of rational drug design try to superimpose putative ligands with a given reference, e.g., an endogenous ligand. The goal of such structural alignments is, on the one hand, to approximate the binding geometry and, on the other hand, to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm981037l
更新日期：1998-11-05 00:00:00
abstract：:Substrate-selective inhibition or modulation of the activity of γ-secretase, which is responsible for the generation of amyloid-β peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical β-peptide foldamers are potent and specific inhibitors of γ-secretas...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301306c
更新日期：2013-02-28 00:00:00
abstract：:To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated produ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00136a007
更新日期：1981-04-01 00:00:00
abstract：:A series of 1-R-5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones was prepared and evaluated for central nervous system depressant activity. Several of these compounds, in particular, 7-chloro-5-ethoxy-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (2), gave a profile and activity level similar to diazepam when measured in mice. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00217a019
更新日期：1977-07-01 00:00:00
abstract：:Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980388x
更新日期：1999-01-14 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：:The alpha- and beta-D-lyxofuranosyl analogues of the naturally occurring nucleosides have been synthesized and their antiviral properties examined. The alpha anomers were prepared by glycosylation of purine and pyrimidine aglycons with tetra-O-acetyl-alpha-D-lyxofuranose, followed by removal of the blocking groups. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00389a005
更新日期：1987-06-01 00:00:00
abstract：:A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic acti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00400a006
更新日期：1988-05-01 00:00:00
abstract：:Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00080a018
更新日期：1992-01-24 00:00:00
abstract：:Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200903z
更新日期：2011-09-08 00:00:00
abstract：:A series of 4- aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole ( metrazole ) and in the rotorod assay for neurologic deficit. For those N-alkyl amides te...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00372a013
更新日期：1984-06-01 00:00:00
abstract：:A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure-activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950721m
更新日期：1996-08-02 00:00:00
abstract：:In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using mo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801385d
更新日期：2009-04-23 00:00:00
abstract：:Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are proglucagon derived peptides that are released from gut endocrine cells in response to nutrient intake. These molecules are rapidly inactivated by the action of dipeptidyl peptidase IV (DPP-4) which limits their use as therapeutic agents. The rece...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.9b00835
更新日期：2020-02-13 00:00:00
abstract：:Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting ma...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020208q
更新日期：2002-10-10 00:00:00
abstract：:The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.8b01767
更新日期：2019-01-10 00:00:00
abstract：:The synthesis of 15 compounds related either to the benz[c]acridine or to the benz[a]acridine series is reported. Spectral data, i.e., NMR and EI fragmentation, are given. These compounds were tested for carcinogenic activity in mice of the XVIInc/Z strain by subcutaneous injection. Only three weak carcinogens were de...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00356a038
更新日期：1983-02-01 00:00:00
