Search

In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.

New stilbene (CAS 56-53-1) derivatives have been synthesized by reductive elimination of desoxybenzoin analogs which were obtained by Fries rearrangement of the corresponding phenolic esters. The chemical structures of the compounds obtained were confirmed by 1 H-NMR, IR and elemental analysis. Anti-implantation activity of the compounds was determined by performing experiments with adult male and female Spargue-Dawley rats of proven fertility. A 67 % inhibition of implantation was observed separately with compounds 3f and 3i.

Bei der Entwicklung moderner Therapien zur Bekampfung von Krebs versucht man, Wirkstoffe spezifisch auf entartete Zellen zu richten und gezielt in molekulare Vorgange einzugreifen, um eine Wechselwirkung mit gesundem Gewebe zu vermeiden. Dieser Artikel zeigt anhand ausgewahlter Beispiele die Arbeitsweise derartiger Strategien. Photodynamische Therapien konnten durch den Einsatz synergetischer Photosensitizer effizienter durchfuhrbar sein. Am Beispiel von tumorspezifischen Antikorpern wird die direkte Applikation von Wirkstoffen bzw. Wirkstoff-aktivierenden Enzymen an die Tumorzelle erlautert. Des Weiteren wird anhand der Signaltransduktionstherapie aufgezeigt, wie durch verschiedene gezielte Eingriffe in zellulare Ablaufe das unkontrollierte Wachstum maligner Zellen unterbunden wird. Gleichen Effekt erhofft man sich von Prozessen, die das Neuwachstum von versorgenden Blutgefasen (Angiogenese) verhindern. Letztlich werden Strategien zur Vermeidung von Medikamentenresistenzen diskutiert und das Konzept der Antisense-Therapie vorgestellt. Modern antitumor therapies involve active agents that specifically target degenerated tissues and interact with molecular processes, while leaving healthy cells untouched. Through the analysis of selected examples, this article describes the mode of operation for these prevailing strategies. Photodynamic therapies could become more effective with the application of synergetic photosensitizers. Tumor-specific antibodies distinguish between the targeted tumor cells and healthy cells and therefore allow the directed administration of agents or drug activating enzymes. Through signal transduction therapy various targeted interventions in cellular sequences can hamper the uncontrolled growth of malignant cells. Processes which prevent the neovascularization (angiogenesis) are expected to have the same effect. Finally strategies to avoid drug resistances are discussed and the concept of antisense therapy is presented.

A systematic study of a ring-closing metathesis towards a tetrasubstituted double bond as part of a seven-membered ring in a 5.7.5-tricyclic guaianolide system is described. By combining two techniques, namely sparging an inert gas through the solution together with dielectric heating via microwave irradiation a high-yielding ring-closing metathesis reaction in this particularly challenging case was achieved. The results obtained compare favorably with conventional heating conditions or with microwave irradiation in a closed system. The key aspects seem to be that rapid microwave irradiation diminishes catalyst decay by allowing the required high reaction temperature to be reached quickly and homogeneously and thereby providing enough energy for a successful metathesis reaction, while inert gas sparging is purging off evolving ethylene to shift the equilibrium to the product.

The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.

Virtual screening in a huge collection of virtual combinatorial libraries has led to the identification of two new structural classes of GPR119 agonists with submicromolar in vitro potencies. Herein, we describe the virtual screening process involving feature trees fragment space searches followed by a 3D postprocessing step. The in silico findings were then filtered and prioritized, and finally, combinatorial libraries of target molecules were synthesized. Furthermore the so-called "activity-anchor principle" is introduced as an element to increase the chance to generate true hits. An activity anchor is a structural element expected to provide key contributions to a certain biological activity. Application of this technique has led to the discovery of two new GPR119-agonist hit series, one of which was further optimized to progress as a novel lead class.

The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.

2,2-Dimethyl-propanedioyl dichloride (l)-Valinol Keywords: bis(4-isopropyloxazoline); ligands; bis(oxazolines); amino alcohols; acid chlorides; condensation; cyclization; tert-leucine; waste disposal

Paraconic acids, belonging to the class of g-butyrolactone natural products, display a broad range of biological activities such as antibiotic and antitumor properties. Consequently a great number of synthetic strategies have been devised for them, ranging from diastereoselective and chiral pool approaches to the application of asymmetric catalysis. This review gives a critical account on the different methods developed that lead to paraconic acids of great structural variety.

The synthesis of E-isomer of 4-Hydroxystilbene and its derivatives 3 by reductive elimination of the carbonyl function in 2-phenyl-1-(4-hydroxyphenyl)ethan-1-one and its derivatives 2 and the X-ray structure of 2a are described.

[reaction: see text] Bicyclic and tricyclic gamma-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps were a copper(I)-catalyzed asymmetric cyclopropanation, Sakurai allylations, intramolecular ene reactions, and ring-closing metathesis reactions.