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. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.

Telmisartan is a potent, long-lasting, nonpeptide antagonist of the angiotensin II type-1 (AT 1 ) receptor that is indicated for the treatment of essential hypertension. It selectively and insurmountably inhibits stimulation of the AT 1 receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. Very high lipophilicity, a unique feature of telmisartan, coupled with a high volume of distribution, indicate that the compound offers the clinically important advantage of good tissue penetration. Telmisartan is not a prodrug and has a longer terminal elimination half-life than other commercially available sartans (~24 h), making it suitable for once-daily dosing. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions. In animal models, telmisartan exhibits pronounced cardioand reno-protective effects in animals with severe, essential hypertension. In clinical studies, telmisartan shows comparable antihypertensive activity to members of other major antihypertensive classes, such as ACE inhibitors, beta blockers and calcium antagonists. These trials have confirmed the placebo-like safety and tolerability of telmisartan in hypertensive patients. Based on these data, telmisartan offers advantages over other sartans and represents an important new treatment option for hypertension.

Telomerase, a ribonucleoprotein acting as a reverse transcriptase, has been identified as a target for cancer drug discovery. The synthetic, non-nucleosidic compound, BIBR1532, is a potent and selective telomerase inhibitor capable of inducing senescence in human cancer cells (1). In the present study, the mode of drug action was characterized. BIBR1532 inhibits the native and recombinant human telomerase, comprising the human telomerase reverse transcriptase and human telomerase RNA components, with similar potency primarily by interfering with the processivity of the enzyme. Enzyme-kinetic experiments show that BIBR1532 is a mixed-type non-competitive inhibitor and suggest a drug binding site distinct from the sites for deoxyribonucleotides and the DNA primer, respectively. Thus, BIBR1532 defines a novel class of telomerase inhibitor with mechanistic similarities to non-nucleosidic inhibitors of HIV1 reverse transcriptase.

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. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

Abstract-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.

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. BIBR 277 potently interacted with rat AT1 receptors (Ki 3.7 nm). Competitive receptor interaction was shown by radioligand saturation experiments performed in the presence of BIBR 277. The failure to inhibit radioligand binding to AT2 sites demonstrates the selectivity of BIBR 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investigated nor affected the activity of components of the human renin‐angiotensin system, such as plasma renin or serum converting enzyme. In rabbit aorta, BIBR 277 had no agonistic properties and was shown to be an insurmountable antagonist of angiotensin II‐induced contractions (KB 0.33 nm). The antagonistic effect persisted even after several wash‐out procedures. However, this interaction was not irreversible since the insurmountable antagonism was concentration‐dependently reversed when BIBR 277 (0.1 μm) and the surmountable antagonist, losartan (0.1 and 1.0 μm) were incubated simultaneously. The specificity of BIBR 277 for the AT1 receptor was further substantiated in this preparation since micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline‐induced contractions nor acetylcholine‐mediated tissue relaxation. In pithed rats, i.v. administration of BIBR 277 (0.1, 0.3 and 1.0 mg kg−1) shifted the dose‐pressor response curve to angiotensin II dose‐dependently to the right with ED50 values of 0.23 μg kg−1 (control) and 1.4 μg kg−1, 4.7 μg kg−1 and 20 μg kg−1, respectively. As observed in the in vitro experiments no agonistic effect was detected and the maximum of the blood pressure response to angiotensin II at the highest dose of BIBR 277 was decreased by 29%. In anaesthetized rats, bolus i.v. administration of 0.1, 0.3 and 1.0 mg kg−1 BIBR 277 attenuated the blood pressure response to bolus i.v. injections of angiotensin II (0.1 μg kg−1). At the highest dose an almost complete blockade was observed even after 2 h. Single oral administration of BIBR 277 (0.3 and 1.0 mg kg−1) to conscious, chronically instrumented renovascular hypertensive rats dose‐dependently decreased the mean arterial blood pressure by 15 and 30 mmHg, respectively. At the higher dose a significant antihypertensive effect was maintained for more than 24 h. Moreover, consecutive daily dosing of 1 mg kg−1 orally resulted in a sustained reduction in blood pressure over the 4 day observation period. It is concluded that BIBR 277 is an effective and selective angiotensin II antagonist with antihypertensive activity after oral administration.

The structural data reveal the molecular basis for a desired unselective inhibition of the two key components of the blood coagulation cascade. The 4-(1-methyl-benzimidazole-2-yl)-methylamino-benzamidine moieties of the inhibitors are able to fill both the small solvent accessible as well as the larger hydrophobic S2 pockets of factor Xa and thrombin, respectively. Distal fragments of the inhibitors are identified which fit into both the cation hole/aromatic box of factor Xa and the hydrophobic aryl binding site of thrombin. Thus, binding constants in the medium-to-low nanomolar range are obtained against both enzymes.