Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces endothelial dysfunction. Here, we examine the participation of endothelial NO synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in endothelial cells from human umbilical cord vein. When cells were treated for 24 h, homocysteine dose-dependently inhibited thrombin-activated NO release without altering eNOS phosphorylation and independently of the endogenous NOS inhibitor, asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release was associated with increased production of reactive nitrogen and oxygen species (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly decreased RNS/ROS formation and the ethidium red fluorescence induced by homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%). In addition, homocysteine suppressed the activating effect of sepiapterin on NO release, but not that of ascorbate. The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.
...
PMID:Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. 1518 55

Since the advent of penicillin, the beta-lactam antibiotics have been the subject of much discussion and investigation, within both the scientific and public sectors. The primary biological targets of the beta-lactam antibacterial drugs are the penicillin binding proteins, a group of transpeptidases anchored within the bacterial cellular membrane, which mediate the final step of cell wall biosynthesis. The extensive use of common beta-lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and beta-lactamase gene transfer. Thus, a handful of nonconventional fused polycyclic beta-lactams have been described in the literature in order to overcome the defence mechanisms of the bacteria. In fact, tricyclic beta-lactam antibiotics, generally referred to as trinems, are a new class of synthetic antibacterial agents featuring good resistance to beta-lactamases and dehydropeptidases. In addition, recent discoveries have shown other biological properties of these compounds apart from their antibacterial action. In this sense, beta-lactams can serve as inhibitors of serine proteases, such as human leukocyte elastase (HLE) or thrombin, acyl-CoA cholesterol acyltransferase inhibitors and inhibitors of human cytomegalovirus. Additional impetus for research efforts on beta-lactam chemistry has been provided by the introduction of the beta-lactam synthon method, a term coined by Ojima 20 years ago, according to which 2-azetidinones can be employed as useful intermediates in organic synthesis. The usefulness of beta-lactams in the stereocontrolled synthesis of heterocycles of biological significance is based on the impressive variety of transformations, which can be derived from this system, due inter alia to a high chirality content that can be transferred into a variety of products. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalisation of the beta-lactam nucleus as a stereocontrolling element. Alternatively, the direct one-pot generation of fused nitrogen heterocyclic systems from the nitrogen framework of 2-azetidinone derivatives has been achieved by selective bond breakage and rearrangement. It is our aim in this Review to highlight the state of the art in this endeavour, consisting either of the stereocontrolled synthesis of fused polycyclic beta-lactams of antibacterial interest, or stereoselective synthesis of different sized heterocycles of biological significance. Representative examples of the latter include indolizidines, pyrrolizidines, pirrolidines, pyrroles, taxoids and macrolide natural products.
...
PMID:Beta-lactams as versatile synthetic intermediates for the preparation of heterocycles of biological interest. 1527 74

The role of vitronectin (Vn) in thrombosis is currently controversial; both inhibitory and supportive roles have been reported. To monitor directly the function of Vn in thrombotic events at the site of vascular injury, we studied Vn-deficient (Vn-/-) and wild-type (WT) control mice with two real-time intravital microscopy thrombosis models. In the mesenteric arteriole model, vessel injury was induced by ferric chloride. We observed unstable thrombi and a significantly greater number of emboli in Vn-/- mice. Vessel occlusion was also delayed and frequent vessel re-opening occurred. In the cremaster muscle arteriole model, vessel injury was induced by a nitrogen dye laser. We observed significantly fewer platelets, lower fibrin content, and unstable fibrin within the thrombi of Vn-/- mice. To define further the role of Vn in thrombus growth, we studied platelet aggregation in vitro. Consistent with our in vivo data, the second wave of thrombin-induced aggregation of gel-filtered platelets was abolished at a low concentration of thrombin in Vn-/- platelets. Interestingly, adenosine diphosphate (ADP)-induced platelet aggregation was significantly increased in Vn-/- platelet-rich plasma (PRP) and this effect was attenuated by adding purified plasma Vn. We also observed increased platelet aggregation induced by shear stress in Vn-/- whole blood. These data demonstrate that Vn is a thrombus stabilizer. However, in contrast to released platelet granule Vn which enhances platelet aggregation, plasma Vn inhibits platelet aggregation.
...
PMID:Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation. 1586 80

This study tested the hypothesis that in humans mild leg exercise affects haemostasis in normobaric hypoxia and thus avoids the development of a deep venous thrombosis (DVT). Eight young men breathed in a 15.4% oxygen in nitrogen gas mixture for 2 hrs while seated at rest (R) or seated and performing a 3-min mild leg exercise program (Ex) at 15-min intervals to assess the impact of mild leg exercise on haemostatic parameters related to the risk of developing DVT, as has been discussed for hypobaric hypoxic conditions during commercial airline travel. Capillary blood gases were analysed every 30 min. Heart rate was monitored continuously. Haemostatic parameters were analysed from venous blood at the beginning, after 1 and 2 hrs, and after a 30-min resting period in normoxic conditions. Plasminogen-activator-inhibitor-1 diminished in both tests in hypoxia, but not after the resting period. Antithrombin-III decreased in R in the hypoxic period. Platelet count, international normalized ratio, partial thromboplastin time remained unchanged, as did highly sensitive parameters like tissue-plasminogen-activator, alpha2-antiplasmin, d-dimers, thrombin-antithrombin-III-complexes, and prothrombin-fragments 1 and 2. The haematocrit decreased significantly in R. The mild leg execise prevented the decrease of antithrombin-III and caused an increase in haematocrit after an initial drop in the first hour. The present study revealed that normobaric hypoxia did not have clinically relevant effects on haemostasis in humans. Mild leg exercise carried out under those conditions did not lead, via alterations in haemostasis, to a reduced risk of DVT.
...
PMID:Effects of mild leg exercise in a seated position on haemostatic parameters under normobaric hypoxic conditions. 1648 21

Sulfamide, a quite simple molecule incorporating the sulfonamide functionality, widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications, may give rise to at least five types of derivatives, by substituting one to four hydrogen atoms present in it, which show specific biological activities. Recently, some of these compounds started to be exploited for the design of many types of therapeutic agents. Among the enzymes for which sulfamide-based inhibitors were designed, are the carbonic anhydrases (CAs), a large number of proteases belonging to the aspartic protease (HIV-1 protease, gamma-secretase), serine protease (elastase, chymase, tryptase, and thrombin among others), and metalloprotease (carboxypeptidase A (CPA) and matrix metalloproteinases (MMP)) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays important roles for the binding of the inhibitor to the active site cavity, either by directly coordinating to a metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors, interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN-SO2-NH motif, which substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-chemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized moiety when attached to an organic scaffold. This interesting motif is thus of great value for the design of pharmacological agents with a lot of applications.
...
PMID:Therapeutic potential of sulfamides as enzyme inhibitors. 1671 Aug 59

A series of 16 tricyclic thrombin inhibitors was prepared by using the 1,3-dipolar cycloaddition of azomethine ylides derived from 3- or 4-hydroxyproline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide as the key step. The terminal pyrrolidine ring of the inhibitors was systematically substituted to explore the potential bioisosteric behavior of C-F, C-OH, and C-OMe residues pointing into the environment of the catalytic center of a serine protease. X-ray crystal structure analyses revealed a distinct puckering preference of this ring. Substitution by F, HO, and MeO has a strong effect on the basicity of the adjacent pyrrolidine nitrogen center which originates from two sigma-inductive pathways between this center and the electronegative O and F atoms. gem-Difluorination decreases the pKa value of this tertiary amine center to <2, making the conjugated ammonium ion a moderately strong acid. Unexpectedly, F substitution next to the nitrogen center reduced the lipophilicity of the ligands, as revealed by measurements of the logarithmic partition coefficient log D. The biological assays showed that all compounds are thrombin inhibitors with activities between Ki=0.08 and 2.17 microM. Bioisosteric behavior of F, HO, and MeO substituents was observed. Their electronegative F and O atoms undergo energetically similar polar interactions with positively polarized centers, such as the N atom of His 57 which is hydrogen bonded to the catalytic Ser 195. However, for energetically similar polar interactions of C-F, C-OH, and C-OMe to occur, sufficient space is necessary for the accommodation of the Me group of the C-OMe residue, and a H-bond acceptor must be present to prevent unfavorable desolvation of the C-OH residue.
...
PMID:A fluorine scan at the catalytic center of thrombin: C--F, C--OH, and C--OMe bioisosterism and fluorine effects on pKa and log D values. 1689 1

This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
...
PMID:Predicting and tuning physicochemical properties in lead optimization: amine basicities. 1753 Jul 27

In the present study some new beta-lactam compounds were screened for their ability to inhibit human platelet activation. In particular four compounds differing in the group on the nitrogen atom of the azetidinone ring were investigated. A beta-lactam having an ethyl 2-carboxyethanoate N-bound group was demonstrated to inhibit, in the micromolar range, both the Ca(2+) release from endoplasmic reticulum, induced either by thrombin or by the ATPase inhibitor thapsigargin, and the Ca(2+) entry in platelets driven by emptying the endoplasmic reticulum. The compound also inhibited the platelet aggregation induced by a variety of physiological agonists including ADP, collagen, thrombin and thrombin mimetic peptide TRAP. The beta-lactam reduced the phosphorylation of pleckstrin (apparent MW 47 kDa), elicited by thrombin but not by the protein kinase C activator phorbol ester. Accordingly it did not significantly affect the aggregation evoked by phorbol ester or Ca(2+) ionophore. It was concluded that the beta-lactam likely exerts its anti-platelet-activating action by hampering the agonist induced cellular Ca(2+) movements. The beta-lactam concentration, which significantly inhibited platelet activation, only negligibly affected the cellular viability. Even if it is still premature to draw definitive conclusions, the present results suggest that this new compound might constitute a tool of potential clinical interest and the starting-point for the synthesis of new more beneficial anti-thrombotic compounds.
...
PMID:Inhibitory effect by new monocyclic 4-alkyliden-beta-lactam compounds on human platelet activation. 1765 5

Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.
...
PMID:Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors. 1805 27

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. In this study, the coagulation status and biochemical and non-specific inflammatory markers in patients with MS were investigated. Plasma prothrombin time, activated partial thrombin time, fibrinogen, D-dimer, serum high sensitive C-reactive protein, homocysteine, blood urea nitrogen, creatinine, calcium, total protein, albumin, total cholesterol, vitamin B12, folate levels and erythrocyte sedimentation rate were measured in 42 patients with MS and 31 healthy subjects as a control group. There was a positive correlation between homocysteine and D-dimer levels (r=0.84, p<0.01). However, there was no significant correlation between homocysteine, vitamin B12 (r=0.18) and folate (r=0.23) levels. Serum total protein, albumin and calcium levels of MS patients were lower than the control group. There are some alterations in the coagulation and biochemical status in MS patients. These findings may contribute to better understanding of the etiopathogenesis and clinical characteristics of this disease.
...
PMID:Coagulation status and biochemical and inflammatory markers in multiple sclerosis. 1825 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---