The discovery of dabigatran etexilate.

Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.

Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin.

Dabigatran is a highly selective, reversible, and potent thrombin inhibitor and is orally available as the prodrug, dabigatran etexilate. It has shown antithrombotic efficacy in animal models of thrombosis, with a rapid onset of action and predictable pharmacodynamic response. Peak plasma concentrations of dabigatran occur 1 to 2 hours after ingestion of the prodrug.

Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity.

Glucuronidation of the carboxylate moiety is the major human metabolic pathway of dabigatran (beta-alanine, N-[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl). It results in the formation of the 1-O-acylglucuronide. Four isomeric acylglucuronides of dabigatran were isolated and purified from urine of dosed rhesus monkeys.

Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.

Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.

Peptidomic analysis of blood plasma after in vivo treatment with protease inhibitors--a proof of concept study.

Native peptides can be regarded as surrogate markers for protease activity in biological samples. Analysis of peptides by peptidomics allows to monitor protease activity in vivo and to describe the influence of protease inhibition. To elucidate the potential of peptides as markers for in vivo protease inhibition we analyzed plasma samples from animals treated with either the indirect FXa inhibitor FONDAPARINUX or the dipeptidylpeptidase IV inhibitor AB192.

Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats.

Dabigatran is a reversible direct, selective thrombin inhibitor, undergoing clinical development as its orally active prodrug, dabigatran etexilate. The objective of this trial was to assess the antithrombotic and anticoagulant effects of dabigatran and dabigatran etexilate in a rat model of venous thrombosis. In order to do this a modified Wessler model was used to assess the antithrombotic and anticoagulant effects of intravenous (i.

In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate.

Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) undergoing advanced clinical development as its orally active prodrug, dabigatran etexilate. This study set out to determine the molecular potency and anticoagulant efficacy of dabigatran and its prodrug dabigatran etexilate. This was achieved through enzyme inhibition and selectivity analyses, surface plasmon resonance studies, platelet aggregation, thrombin generation and clotting assays in vitro and ex vivo.

Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis.

Background: Oral anticoagulant therapies targeted at thrombin are being developed to overcome limitations associated with current standard therapies.

Objectives: This study was undertaken to assess and compare the antithrombotic and anticoagulant effects of the novel, selective and reversible, direct thrombin inhibitor (DTI), dabigatran, and its oral prodrug dabigatran etexilate, to that of unfractionated heparin (UFH), hirudin and melagatran using a rabbit model of venous thrombosis.

Methods: A rabbit model of venous thrombosis consisting of endothelial damage with blood flow reduction was used with minor modifications.

Heterocyclic thrombin inhibitors. Part 2: quinoxalinone derivatives as novel, potent antithrombotic agents.

Quinoxalinone derivatives as prototypes of dual thrombin and factor Xa inhibitors have been discovered. Nanomolar inhibition of both coagulation enzymes resulted in very potent antithrombotic activity in vitro.

Heterocyclic thrombin inhibitors. Part 1: design and synthesis of amidino-phenoxy quinoline derivatives.

Amidino-phenoxy quinoline derivatives represent a new class of potent thrombin inhibitors with good selectivity and remarkably low molecular weight (M(W): 335-391). X-ray analyses of thrombin-bound inhibitors revealed that enzyme inhibition is mainly based on hydrophobic interactions.

In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist.

In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype.

Characterization and comparative evaluation of a novel PAI-1 inhibitor.

Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator in plasma, is a well established risk factor in thrombotic diseases. Reduction of active PAI-1 levels may lead to a decreased tendency of thrombosis. Compounds that can suppress pharmacologically active PAI-1 levels are therefore considered as putative drugs.

Structure-based design of novel potent nonpeptide thrombin inhibitors.

The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme.

Effects of telmisartan, hydrochlorothiazide and their combination on blood pressure and renal excretory parameters in spontaneously hypertensive rats.

The effects of telmisartan and hydrochlorothiazide (HCTZ) alone and in combination on blood pressure (BP) and renal excretory function were investigated in male spontaneously hypertensive rats (SHR) after oral administration for five consecutive days. Four treatments were studied: vehicle (0.5% Natrosol), telmisartan 3 mg/kg, HCTZ 10 mg/kg, and telmisartan 3 mg/kg+HCTZ 10 mg/kg.

Comparative antihypertensive and renoprotective effects of telmisartan and lisinopril after long-term treatment in hypertensive diabetic rats.

This study compared the cardiovascular and renal effects of long-term telmisartan (3 and 10 mg/kg/day)and lisinopril (10 mg/kg/day) in an animal model combining hypertension and diabetes mellitus. It was a parallel-group study of diabetic, spontaneously hypertensive rats (SHR), treated with control or active treatment for eight months. A non-diabetic SHR control group was run in parallel.

AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats.

The effects of systemic treatment with the AT1 receptor antagonist telmisartan on central effects of angiotensin II (Ang II), namely, increase in blood pressure, vasopressin release into the circulation, and drinking response, were investigated in conscious, normotensive rats. The central responses to i.c.

Effects of telmisartan on renal excretory function in conscious dogs.

The present study investigated the effects of telmisartan, a selective AT1 receptor antagonist, on renal function in dogs. Conscious female dogs were treated with (i) vehicle (controls) and three doses of telmisartan (0.03 mg/kg, 0.

Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors.

Background: A major current focus of pharmaceutical research is the development of selective inhibitors of the blood coagulation enzymes thrombin or factor Xa to be used as orally bioavailable anticoagulant drugs in thromboembolic disorders and in the prevention of venous and arterial thrombosis. Simultaneous direct inhibition of thrombin and factor Xa by synthetic proteinase inhibitors as a novel approach to antithrombotic therapy could result in potent anticoagulants with improved pharmacological properties.

Results: The binding mode of such dual specific inhibitors of thrombin and factor Xa was determined for the first time by comparative crystallography using human alpha-thrombin, human des-Gla (1--44) factor Xa and bovine trypsin as the ligand receptors.

Effects of an angiotensin II antagonist on organ perfusion during the post-resuscitation phase in pigs.

BACKGROUND: The aim of this study was to compare pre-arrest and post-resuscitation organ perfusion values and to investigate whether, during the post-resuscitation phase, administration of the angiotensin II antagonist telmisartan (TELM) 10 min after restoration of spontaneous circulation (ROSC) could improve organ flow in comparison to placebo. RESULTS: Five minutes after ROSC in the TELM group, blood flow in the cortex and myocardium increased to 583% (P < 0.05) and 137% (not significant), respectively, whereas blood flow of the colon, stomach and pancreas decreased to 50% (P < 0.

Effect of angiotensin II and telmisartan, an angiotensin1 receptor antagonist, on rat gastric mucosal blood flow.

Background: Angiotensin II (ATII) has been suggested to contribute to shock-induced dysfunction of the gastric circulation.

Aim: To substantiate this conjecture, the effects on gastric mucosal haemodynamics and the hyperaemic response to acid back-diffusion of ATII and the angiotensin AT1 receptor antagonist, telmisartan, were examined in normal rats and in animals subjected to haemorrhage.

Methods: Gastric mucosal blood flow in phenobarbital-anaesthetized rats was recorded with the hydrogen clearance technique, and acid back-diffusion was induced by perfusing the stomach with ethanol (25%) in HCl (0.

Effects of AT1 receptor blockade on blood pressure and the renin-angiotensin system in spontaneously hypertensive rats of the stroke prone strain.

The aim of the study was to assess the effects of chronic angiotensin I receptor blockade on blood pressure, the renin-angiotensin system in plasma and kidney and the extent of renal damage in spontaneously hypertensive rats of the stroke prone strain (SHRsp). Four months old male SHRsp rats were orally treated with a high (10 mg/kg b.w.

Effects of the AT1-selective angiotensin II antagonist, telmisartan, on hemodynamics and ventricular function after cardiopulmonary resuscitation in pigs.

The purpose of this study was to investigate the effects of the angiotensin II (ANG II) antagonist, telmisartan, on hemodynamics, myocardial function and myocardial blood flow during the postresuscitation phase in a porcine model of CPR and to compare these to saline. After 4 min of ventricular fibrillation and 5 min of closed-chest CPR, defibrillation was performed in 16 domestic pigs to restore spontaneous circulation (ROSC). Ten minutes after ROSC, animals were allocated to receive either the ANG II antagonist, telmisartan, at a dose of 1 mg/kg (n = 8) or saline (n = 8).

Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade.

TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with antihypertensive and non-antihypertensive doses of the angiotensin II receptor AT1 antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles.

BIBP 3226, the first selective neuropeptide Y1 receptor antagonist: a review of its pharmacological properties.

Based on the assumption that the pharmacophoric groups interacting with the Y1 receptor are located in the C-terminal part of neuropeptide Y, low molecular weight compounds with high affinity and selectivity for the Y1 receptor were designed and synthesized. The prototype BIBP 3226 possesses affinity for the Y1 receptor in the nanomolar range. In addition, this compound is selective displaying rather low affinity for Y2, Y3, Y4 and a set of 60 other receptors.

Subtype selectivity and antagonistic profile of the nonpeptide Y1 receptor antagonist BIBP 3226.

In the present study, the subtype specificity and species selectivity of the nonpeptide BIBP 3226, as well as its in vitro antagonism of neuropeptide Y (NPY)-mediated second messengers have been investigated. Radiolabeled NPY is potently displaced by BIBP 3226 [(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenylmethyl]-D- arginine amide] on human Y1 receptor expressing Chinese hamster ovary-K1 cells (Ki = 0.47 +/- 0.