Abstract:
:The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Singh J,Zeller W,Zhou N,Hategan G,Mishra RK,Polozov A,Yu P,Onua E,Zhang J,Ramírez JL,Sigthorsson G,Thorsteinnsdottir M,Kiselyov AS,Zembower DE,Andrésson T,Gurney MEdoi
10.1021/jm9005912subject
Has Abstractpub_date
2010-01-14 00:00:00pages
18-36issue
1eissn
0022-2623issn
1520-4804journal_volume
53pub_type
杂志文章abstract::The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete co...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950596e
更新日期:1996-10-25 00:00:00
abstract::The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the va...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b01575
更新日期:2017-07-13 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::The diester 2a obtained from 1,1'-ferrocenedicarboxylic acid and the highly and indiscriminately cytotoxic fungal metabolite illudin M (1) displayed antiproliferative activity at submicromolar IC(50) (72 h) values against a panel of eight cancer cell lines. Compound 2a was about 40 times less toxic than 1 to nonmalign...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200359n
更新日期:2011-09-22 00:00:00
abstract::Sulfur mustard (SM) is a highly toxic chemical warfare agent. A satisfactory treatment regimen is not yet available for this toxicant. In a search for an effective antidote against SM, a series of novel S-2(omega-aminoalkylamino)ethyl alkyl/aryl thioethers [H(2)N(CH(2))(n)()NHCH(2)CH(2)SR], where R = alky, alicyclic, ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030099v
更新日期:2004-07-15 00:00:00
abstract::For a fourth approach of quinoxaline N,N'-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing subst...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm2002469
更新日期:2011-05-26 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::Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5014743
更新日期:2014-11-26 00:00:00
abstract::A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher wi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900458r
更新日期:2009-12-10 00:00:00
abstract::Analogues of the potent inhibitor of choline acetyltransferase (CAT) (E)-4-(1-naphthylvinyl)pyridine methiodide were synthesized and evaluated for their ability to inhibit CAT and protect against nerve agent intoxication. Several compounds, notably (E)-1-(2-hydroxyethyl)-(1-naphthylvinyl)pyridinium bromide (3), (E)-1-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00399a022
更新日期:1988-04-01 00:00:00
abstract::We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9804127
更新日期:1998-12-03 00:00:00
abstract::Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980620z
更新日期:1999-08-26 00:00:00
abstract::The synthesis of two new series of dicarboxylic acid dipeptides and two sulfhydryl-containing inhibitors are described. The in vitro enkephalinase inhibition data and some in vivo analgesic data are presented for these compounds. For the dibenzylglutaric acid series structure-activity relationships and in vivo analges...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00132a005
更新日期:1989-12-01 00:00:00
abstract::G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b01601
更新日期:2017-05-25 00:00:00
abstract::A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were prepared as potential peroxide antimalarial agents. In both series of cyclic peroxides, the steric and electronic effects of the substituents attached to the peroxide ring exert a remarkable influence on the antimalarial activity. For some cycli...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990014j
更新日期:1999-07-15 00:00:00
abstract::Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049383s
更新日期:2005-04-21 00:00:00
abstract::The importance of inhibitors of glycosidases as therapeutic agents for viral, proliferative, and metabolic diseases is being increasingly recognised. Several years ago we reported that the activities of mannosidase inhibitors may be explained in terms of their similarity to the mannosyl cation intermediate postulated ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960237z
更新日期:1996-10-11 00:00:00
abstract::A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01982
更新日期:2016-03-10 00:00:00
abstract::Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm021028j
更新日期:2003-04-10 00:00:00
abstract::Novel substituted benzoyl benzoic acids and phenylacetic acids 1-14 have been synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC(50) values in the nanomolar range. The phe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050728w
更新日期:2006-01-26 00:00:00
abstract::As part of a continuing search for specific inhibitors of the enzymes involved in polyamine biosynthesis, we have designed and synthesized a multisubstrate adduct inhibitor, S-adenosyl-1,12-diamino-3-thio-9-azadodecane (AdoDATAD), in which critical portions of the nucleophilic aminopropyl acceptor are covalently linke...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00126a026
更新日期:1989-06-01 00:00:00
abstract::N-Piperidinopropyl-galanthamine (2) and N-saccharinohexyl-galanthamine (3) were used to investigate interaction sites along the active site gorge of Torpedo californica actylcholinesterase (TcAChE). The crystal structure of TcAChE-2 solved at 2.3 A showed that the N-piperidinopropyl group in 2 is not stretched along t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901296p
更新日期:2010-01-28 00:00:00
abstract::Endothelin-converting enzyme-2 (ECE-2), a member of M13 family of zinc metallopeptidases, has previously been shown to process a number of neuropeptides including those derived from prodynorphin, proenkephalin, proSAAS, and amyloid precursor protein. ECE-2, unlike ECE-1, exhibits restricted neuroendocrine distribution...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm7015478
更新日期:2008-06-26 00:00:00
abstract::With the aim of increasing therapeutic indexes of novel cyclic depsinonapeptide pseudomycins, we synthesized and evaluated a series of mono-, di-, and trioxodioxolenylmethyl carbamate prodrugs (2 and 4) of pseudomycin B 1 and pseudomycin C' 3. It is rather encouraging to note that several members of the newly synthesi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000425w
更新日期:2001-08-02 00:00:00
abstract::We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the 4-keto-1,2-oxathiole-2,2-dioxide (beta-keto-gamma-sultone) heterocyclic system. Several 4- and 5-substituted-5H-1,2-oxathiole-2,2-dioxide derivatives were found to have a selective inhibitory activity against ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8014662
更新日期:2009-03-26 00:00:00
abstract::Structure-activity relationship studies of substituted arylsulfoanilides as antiproliferatives, which are mediated by the partial depletion of intracellular Ca(2+) stores, resulted in the identification of compounds with micromolar activity against lung cancer cells in a growth inhibition assay. Incorporating the subs...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0496234
更新日期:2004-10-07 00:00:00
abstract::The directional properties of hydrogen bonds play a major role in determining the specificity of intermolecular interactions. An energy function which takes explicit account of these properties has been developed for use in the determination of energetically favorable ligand binding sites on molecules of known structu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00053a018
更新日期:1993-01-08 00:00:00
abstract::Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor act...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9700981
更新日期:1997-10-10 00:00:00
abstract::Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00068a001
更新日期:1993-08-06 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