Abstract：
:C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin. In this paper, a series of synthetic peptides were prepared by solid-phase methodology to determine the optimal N-terminal and position 56 functionalities for these C-terminal fragment analogues of hirudin. Inhibition of fibrin clot formation by thrombin in vitro was used as a measure of anticoagulant activity. In the minimal C-terminal sequence necessary for anticoagulant activity, hirudin56-64, an L aromatic amino acid is required at position 56. Phe56----Tyr substitution retained potency, whereas p-Cl-Phe56 and phenylglycine56 substitutions resulted in decreased potencies. Removal of the cationic amino functionality from the vicinity of Asp55 results in increased potency (e.g., hirudin54-65, Ac-hirudin55-65) and [desNH2-Asp55]hirudin55-65 has a marked increase in potency over hirudin55-65. [DesNH2-Phe56]hirudin56-65 and related analogues show no detectable anticoagulant activity. The sensitivity of position 56 to modification demonstrates the significance of this residue in the interaction between the C-terminal region of hirudin and thrombin.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Owen TJ,Krstenansky JL,Yates MT,Mao SJdoi
10.1021/jm00400a020subject
Has Abstractpub_date
1988-05-01 00:00:00pages
1009-11issue
5eissn
0022-2623issn
1520-4804journal_volume
31pub_type
杂志文章abstract：:Two separate libraries, prepared via parallel synthesis, were employed to identify low-molecular-weight SH2-targeted ligands for the Lck tyrosine protein kinase. These libraries were constructed to furnish non-amino acid analogues of the (1) Glu-Glu and (2) Ile residues of the Lck SH2 domain peptide ligand Ac-pTyr-Glu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990462r
更新日期：2000-03-23 00:00:00
abstract：:Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00243a021
更新日期：1975-09-01 00:00:00
abstract：:A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A(3) adenosine receptor antagonists, is described. The compounds represent an extension and an improvement of our previous work on this class of compou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0109614
更新日期：2002-02-14 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：:The C-terminal "address" sequences of prodynorphin-derived opioid peptides contain an unusually high proportion of basic residues, which are known to be crucial for conferring high activity and selectivity for kappa-opioid receptors. In an effort to investigate the possibility that the polycationic "tails" may be invo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00113a020
更新日期：1991-09-01 00:00:00
abstract：:The major mechanism by which the serotonin neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) expresses its neurodegenerative action may involve alkylation of biological nucleophiles by the electrophilic quinoid autoxidation products. To determine the relative importance of various sites on these autoxidation products towar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00147a027
更新日期：1985-09-01 00:00:00
abstract：:Opical antipodes of the axial phenyl analgetic, alpha-promedol hydrochloride (3), were prepared and the absolute stereochemistry wasd determined by relating one of the enantiomers to its gamme diastereomer having the 2S, 4S,5R configuration. The analegetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, whil...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00231a014
更新日期：1976-09-01 00:00:00
abstract：:The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or 6-position of one indole ring increase or preserve potency, whereas most modifications of the ring structures and of the methanone ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010988n
更新日期：2002-02-28 00:00:00
abstract：:A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a017
更新日期：1984-09-01 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：:Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00366a004
更新日期：1983-12-01 00:00:00
abstract：:Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous environment, which has a negative influence on their photosensitizing ability in photodynamic therapy. Pcs with either peripheral or axial solketal substituents, that is, ZnPc(sol)8 and Si(sol)2Pc, respectively, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061136w
更新日期：2007-04-05 00:00:00
abstract：:The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00473
更新日期：2015-06-11 00:00:00
abstract：:[4-Threonine, 7-glycine]oxytocin and [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin) were synthesized by a combination of solid-phase and classical methods of peptide synthesis. A protected octapeptide was synthesized by the solid-phase method and following ammo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00211a025
更新日期：1977-01-01 00:00:00
abstract：:Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500782s
更新日期：2014-11-26 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00121a027
更新日期：1989-01-01 00:00:00
abstract：:Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200803d
更新日期：2011-09-22 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991099r
更新日期：1999-12-30 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00390a022
更新日期：1987-07-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00184
更新日期：2015-06-11 00:00:00
abstract：:The tetrapeptide H-Arg-Gly-Asp-Ser-OH (1) (RGDS), representing a recognition sequence of fibrinogen for its platelet receptor GP IIb-IIIa (integrin alpha IIb beta 3), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-terminal arginine by p-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00101a017
更新日期：1992-11-13 00:00:00
abstract：:A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00024a008
更新日期：1995-11-24 00:00:00
abstract：:Lymphatic filariasis (elephantiasis) is a global public health problem caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. We have previously reported anthraquinones from daylily roots with potent activity against pathogenic trematode Schistosoma mansoni. Here we report the synthesis of novel ant...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492655
更新日期：2005-04-21 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00066a011
更新日期：1993-07-09 00:00:00
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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
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00084a011
更新日期：1992-03-20 00:00:00
abstract：:N-Methylation of two retinoidal amide compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (3, Am80) and 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carbonyl]amino]benzoic acid (5, Am580), resulted in the disappearance of their potent differentiation-inducing act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00130a011
更新日期：1989-10-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030524k
更新日期：2004-07-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950592+
更新日期：1996-02-16 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
