Abstract:
:The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Chackalamannil S,Wang Y,Greenlee WJ,Hu Z,Xia Y,Ahn HS,Boykow G,Hsieh Y,Palamanda J,Agans-Fantuzzi J,Kurowski S,Graziano M,Chintala Mdoi
10.1021/jm800180esubject
Has Abstractpub_date
2008-06-12 00:00:00pages
3061-4issue
11eissn
0022-2623issn
1520-4804journal_volume
51pub_type
杂志文章abstract::Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00210a028
更新日期:1978-12-01 00:00:00
abstract::A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3-arylquinoxalines were prepared and tested for inhibition of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950727b
更新日期:1996-05-24 00:00:00
abstract::Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010090y
更新日期:2001-10-11 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
abstract::A series of cis- and trans-6,6a,7,8,9,10,10a,11-octahydro-11- oxodibenzo[b,e]thiepinacetic acids (6-9) and -oxepinacetic acids (10-13) were prepared and their antiinflammatory activity was examined in the rat carrageenan hind paw edema test. The antiinflammatory activity of these compounds depended on their stereochem...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00164a006
更新日期:1990-02-01 00:00:00
abstract::To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501552x
更新日期:2014-12-11 00:00:00
abstract::Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGF...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01894
更新日期:2017-04-13 00:00:00
abstract::A facile procedure is described for the conversion of morphine, via the diphosphate ester derivative 1 followed by catalytic reduction and treatment with Li/NH3, to 3-deoxy-7,8-dihydromorphine (3). Oxidation with benzophenone tert-butoxide converted 3 to the ketone 4, which on treatment with Zn/NH4Cl formed (-)-4-hydr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00144a013
更新日期:1981-12-01 00:00:00
abstract::Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990252e
更新日期:2000-06-15 00:00:00
abstract::(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)thymine (DOT) is the first thymidine kinase-activated nucleoside that is significantly active against all of the clinically significant NRTI-resistant HIV-1 mutants, including AZT (D67N/K70R/T215Y/K219Q), Tenofovir (K65R), and Lamivudine (M184V). To understand the molec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050060l
更新日期:2005-06-16 00:00:00
abstract::Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is an enzyme involved in thymidine metabolism and homeostasis, and its catalytic activity appears to play an important role in angiogenesis. Here we describe the cloning and expression of a His-tagged human TP/PD-ECGF and its assay wi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000037u
更新日期:2000-06-29 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::A series of novel, disulfide-constrained human beta-melanocyte stimulating hormone (beta-MSH)-derived peptides were optimized for in vitro melanocortin-4 receptor (MC-4R) binding affinity, agonist efficacy, and selectivity. The most promising of these, analogue 18, was further studied in vivo using chronic rat food in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0501432
更新日期:2005-05-05 00:00:00
abstract::Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizure...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00019a019
更新日期:1995-09-15 00:00:00
abstract::New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement wa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010863i
更新日期:2001-08-30 00:00:00
abstract::A series of acyclic analogues of 2'-deoxynucleosides related in structure to 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) have been synthesized and evaluated for antiviral activity against herpes simplex virus type 1 (F strain). Additionally, the ability of these analogues to function as substrates for the vir...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00381a015
更新日期:1985-03-01 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::Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and con...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b00551
更新日期:2016-11-10 00:00:00
abstract::A series of 4(6)- and 5-phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines were prepared and evaluated for central nervous system (CNS) effects in animal models. Several 5-phenyl-substituted compounds possessed potent antidepressant activity and all compounds in this series were de...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00383a002
更新日期:1985-06-01 00:00:00
abstract::A series of 3-(alkoxymethyl)-alpha-(N-substituted aminomethyl)-4-hydroxybenzyl alcohols was synthesized as potential bronchodilators. The ability to prevent effects against histamine-induced bronchoconstriction in guinea pigs was studied to determine their bronchodilating activity. Introduction of a methoxymethyl grou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00189a012
更新日期:1979-03-01 00:00:00
abstract::The recent discovery that the formaldehyde conjugates of doxorubicin and daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast cancer cells prompted the search for hydrolytically more stable anthracycline-formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the parent dru...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970739s
更新日期:1998-04-09 00:00:00
abstract::3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antag...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00074a021
更新日期:1993-10-29 00:00:00
abstract::A conceptionally new 3D molecular descriptor type and methodology are deduced by simple statistical thermodynamic reasoning, based on the free energy change encountered during a transformation of a conformational ensemble of the ligand to an active conformation. The performance of the descriptor was first tested on 37...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049157i
更新日期:2005-05-05 00:00:00
abstract::c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm502018y
更新日期:2015-03-12 00:00:00
abstract::Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by eva...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701275z
更新日期:2008-04-10 00:00:00
abstract::5-Alkyl- and 5-arylalkyl-3-methylenedihydrofuran-2-ones 13a-e, 3-alkylidenedihydrofuran-2-ones 18a-c, and 3-methylenepyrrolidin-2-ones 16a-e were synthesized utilizing ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 9a-e as common intermediates. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm048970a
更新日期:2005-05-19 00:00:00
abstract::The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049500j
更新日期:2005-04-21 00:00:00
abstract::Quantitative structure-activity relationships of the Hansch-type were developed to account for inhibition of thymidine kinases from Herpes simplex viruses types 1 and 2 (HSV1,2) by N2-phenylguanines. Derivatives with meta and/or para substituents on the phenyl ring display a wide range of overlapping, but not identica...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00094a007
更新日期:1992-08-07 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::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