Abstract:
:We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lu T,Markotan T,Ballentine SK,Giardino EC,Spurlino J,Crysler CS,Brown K,Maryanoff BE,Tomczuk BE,Damiano BP,Shukla U,End D,Andrade-Gordon P,Bone RF,Player MRdoi
10.1021/jm901802nsubject
Has Abstractpub_date
2010-02-25 00:00:00pages
1843-56issue
4eissn
0022-2623issn
1520-4804journal_volume
53pub_type
杂志文章,随机对照试验abstract::A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adren...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00192a023
更新日期:1979-06-01 00:00:00
abstract::A large number of methods are available for modeling quantitative structure-activity relationships (QSAR). We examine the predictive accuracy of several methods applied to data sets of inhibitors for angiotensin converting enzyme, acetylcholinesterase, benzodiazepine receptor, cyclooxygenase-2, dihydrofolate reductase...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0497141
更新日期:2004-10-21 00:00:00
abstract::Although the majority of proteins used for biomedical research are produced using living systems such as bacteria, biological means for producing proteins can be advantageously complemented by protein semisynthesis or total chemical synthesis. The latter approach is particularly useful when the proteins to be produced...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01082
更新日期:2020-12-24 00:00:00
abstract::Prolonged drug-target occupancy has become increasingly important in lead optimization, and biophysical assays that measure residence time are in high demand. Here we report a practical label-free assay methodology that provides kinetic and affinity measurements suitable for most target classes without long preincubat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01829
更新日期:2018-06-28 00:00:00
abstract::In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma w...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00698
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abstract::N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be u...
journal_title:Journal of medicinal chemistry
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doi:10.1021/acs.jmedchem.5b01510
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abstract::9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300642a
更新日期:2013-03-14 00:00:00
abstract::A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401899x
更新日期:2014-05-22 00:00:00
abstract::The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes. To gain insight into their mechanism of action, the crystal structure of the canonical oxazolidinone, linezolid, has been determined bound to the Haloarcula marismortui 50S subunit. Linezolid binds the 50S A-site, near the catalytic cent...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800379d
更新日期:2008-06-26 00:00:00
abstract::Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. ...
journal_title:Journal of medicinal chemistry
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更新日期:2015-03-26 00:00:00
abstract::Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049614v
更新日期:2005-03-24 00:00:00
abstract::Dideoxy- and trideoxynucleosides of 5-fluorouracil have been synthesized for antitumor evaluation. 2',5'-Dideoxy-5-fluorouridine (3) was prepared from 2'-deoxy-5-fluorouridine (1) by iodination using methyltriphenoxyphosponium iodide, followed by catalytic reduction. 1-(2',5'-Dideoxy-beta-D-threo-pentofuranosyl)5-fluo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00182a008
更新日期:1980-08-01 00:00:00
abstract::Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfenta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00126a040
更新日期:1989-06-01 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::While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00033
更新日期:2017-03-09 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::Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900697r
更新日期:2009-11-12 00:00:00
abstract::We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had com...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01204
更新日期:2016-11-23 00:00:00
abstract::The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. L...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0496133
更新日期:2004-09-23 00:00:00
abstract::Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound als...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901230r
更新日期:2009-11-26 00:00:00
abstract::Utilizing NNC 26-9100 (11) as a structural lead, a variety of nonpeptide derivatives of somatostatin were synthesized and evaluated for sst2 and sst4 receptor binding affinity. A novel thiourea scaffold was utilized to attach (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:1998-11-19 00:00:00
abstract::Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:1990-09-01 00:00:00
abstract::In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2004-06-03 00:00:00
abstract::The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, res...
journal_title:Journal of medicinal chemistry
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abstract::A series of 3-methyl-3-(m-hydroxyphenyl)piperidines with N-substituent variations have been synthesized and resolved, and an X-ray crystal structure of one analogue was determined. The compounds have been characterized, pharmacologically, by detailed opiate receptor binding studies and determination of in vivo analges...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00154a018
更新日期:1986-04-01 00:00:00
abstract::The N- and C-terminal domains of human somatic angiotensin I converting enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates was...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2013-12-27 00:00:00
abstract::A number of new 4(1H)-quinazolinones were synthesized and evaluated in the carrageenin-induced paw edema test. Most of the compounds were obtained by the cyclization of the appropriately substituted anthranilamides with acid chlorides, followed by further chemical transformation. Structure-activity data suggest that 2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm50001a006
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abstract::To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecul...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2006-07-13 00:00:00
abstract::One of the pattern recognition techniques, the SIMCA method, has been applied to structure-taste studies on L-aspartyl dipeptides (L-Asp-NH-R). The sweet and bitter taste class models of the peptides were obtained by using five structural descriptors, such as molar refractivity, and four kinds of STERIMOL parameters. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00156a006
更新日期:1986-06-01 00:00:00
abstract::The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bind to HRV serotype 14 3CP with inhibition activities (kobs/[I]) r...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980068d
更新日期:1998-07-16 00:00:00