Ligand-Accelerated Stereoretentive Suzuki-Miyaura Coupling of Unprotected 3,3'-Dibromo-BINOL.

An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm.

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.

Factor Xa inhibitors--a review of the recent patent literature.

This review covers the patent literature and related scientific reports in the field of factor Xa inhibitors published between January 1999 and June 2000. During this time, the amount of scientific information as well as the number of newly published patent applications has continuously increased. It is the aim of this review to give an overview of the different structural types of factor Xa inhibitors, to clarify the relationship between newly claimed and previously known inhibitors, and assess the clinical potential of the different factor Xa inhibitors.

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.

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.

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.

6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships.

Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats.

Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277.

1. The pharmacological profile of BIBR 277, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl ]- [1,1'-biphenyl]-2-carboxylic acid, a novel, nonpeptide angiotensin II receptor antagonist has been investigated by use of receptor binding studies, enzymatic assays, functional in vitro assays in rabbit aorta as well as in vivo experiments in pithed, anaesthetized and conscious rats. 2.

Angiotensin II receptor antagonists.

The development of novel non-peptide compounds with high affinity for-angiotensin II (Ang II) receptors has greatly facilitated the subclassification of Ang II receptors into AT1- and AT2-receptor subtypes. Whereas PD 123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenyl-acetyl-4,5,6,7-tetrahydro- 1H-imidazol [4,5-c]pyridine-6-carboxylic acid) is the prototypical antagonist for AT2-receptors, DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl) imidazole, losartan) is the prototypical antagonist for AT1-receptors. So far, non-selective non-peptide Ang II receptor antagonists have not been identified although AT1/AT2 selectivity ratios of 17 and 37 have already been reported for BIBS 39 (4'-[(2-n-butyl-6- cyclohexylaminocarbonylamino-benzimidazole-1-yl)-methyl] biphenyl-2-carboxylic acid) and BIBS 222 (2-n-butyl-1-[4-(6-carboxy-2, 5-dichlorobenzoylamino)-benzyl]-6-N-(methylaminocarbonyl)- n-pentylaminobenzimidazole).

Synthesis of alkylphosphonates, a new class of antineoplastic agents.

Three different phosphonate analogues of hexadecylphosphocholine, a representative of a new class of antineoplastic agents, were synthesized. The structures of the newly synthesized compounds have been devised to contain only one cleavage point for either phospholipase C or phospholipase D. These structural features should allow an examination of the importance of these enzymes for the antineoplastic activities of alkylphosphocholines.

Synthetic phospholipids as substrates for phospholipase C from Bacillus cereus.

The substrate requirement of phospholipids for hydrolysis with phospholipase C from Bacillus cereus was studied with synthetic lipids well-defined in structure and configuration. For optimal activity, the glycerol molecule must contain three substituents: phosphocholine in sn-3-, an ester bond in sn-2- and an ether- or ester bond in sn-1-position. The length of the ester or ether chains is of minor importance.

In vitro and in vivo antitumoral activity of alkylphosphonates.

Hexadecylphosphocholine is a new antitumour agent with a highly selective activity in chemically induced mammary tumours. It was suggested, that hexadecylphosphocholine is a pro-drug, cleavable by phospholipases C and/or D, creating hexadecanol or hexadecylphosphate as the active principle. To test this hypothesis, the antineoplastic activity of three alkylphosphonates, cleavable either by phospholipase C or D, are compared with those of the parent compound, hexadecylphosphocholine.