Technology Offerings

Adenosine is a modulator of many physiological and pathophysiological processes in the central nervous system (CNS). Blockade of the adenosine receptors A1ARs and A2AARs has shown beneficial neuroprotective effects in animal models and in clinical studies of Parkinsons’s disease (PD) and Alzheimer’s disease (AD). There is still no satisfactory multitarget drug approach which inhibits MAO-A and the two adenosine receptors A1ARs and A2AARs. This invention provides newly designed tricyclic xanthine derivatives which allow overcoming this problem. A variety of 69 derivatives were prepared and evaluated in radioligand binding studies at adenosine receptors and for their ability to inhibit monoamine oxidases. Potent dual-target-directed A1/A2A adenosine receptor antagonists were identified. Several compounds even showed triple-target inhibition.

The co-stimulatory CD40-CD40L dyad is crucial in the development and progression of immune responses and chronic inflammatory diseases, such as atherosclerosis, obesity and multiple sclerosis. However, long-term antibody-mediated inhibition of CD40L or CD40 is not clinically feasible as it results in thromboembolic events and severe immune suppression. More downstream inhibition of the CD40L-CD40 pathway is therefore preferable, especially tumor necrosis factor receptor-associated factors (TRAFs) recruited by CD40. Here we created a set of inhibitors that selectively block CD40-TRAF6 interactions. The rest of the CD40 cascade is left unaffected preventing unwanted immune-suppressive side effects. Therefore, our new inhibitors offer promising candidates as therapeutic agents for the treatment of chronic inflammatory diseases, such as atherosclerosis, obesity and multiple sclerosis.

Experiments at the University of Bonn have shown that the expression of MED15, a subunit of the trans-criptional co-regulator Mediator, correlates with the proliferative activity of cells. MED15 is essential for TGF-ß-signaling and control of cholesterol/lipid homeostasis. The protein shows low frequency in androgen-sensitive prostate cancer and lacks expression in benign prostatic tissue.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide (sulfatide), in the nervous system and various other organs. In patients, lipid storage causes a progressive loss of myelin leading to various neurological symptoms. The sulfatide storage in ASA-deficient mice is comparable to humans, but the mice do not mimic the myelin pathology.
Therefore, transgenic ASA-deficient (tg/ASA(-/-)) mice were generated overexpressing the sulfatide-synthesizing enzyme galactose-3-O-sulfotransferase.

Tool coils for or magneforming (or electromagnetic forming = EMF) of complex, 3D shaped parts were previously wound from wires or produced by complex
processes such as milling and wire eroding. The milling process is necessary to produce the outer contour. Wire eroding is used to create the winding structures,
whereby it should be noted, that a 3D design is very limited. The invention concerns to special coils
for EM forming and for a method for their production, wherein the current-carrying coil body is additively manufactured using a rapid prototyping method (laser
melting, etc.).

<b>Background</b>
Protein kinase C zeta (PKCζ) is implicated in the development of several inflammatory diseases and a promising therapeutic target. PKCζ controls TH2 response and is important for the regulation of NF-κB transcriptional activity. Moreover, there is increasing evidence for an involvement of PKCζ in tumor development, where it controls chemoresistance and cancer–related inflammation.

<b>Invention</b>
Scientists of Saarland University and German University in Cairo have discovered 1,3,5-trisubstituted and 1,3,4,5-tetrasubstituted pyrazolines as a potent and selective class of allosteric PKCζ inhibitors. Several of the compounds show inhibitory activity in the nanomolar range. The compounds have an allosteric mode of action by binding the less conserved PIF pocked domain and are highly selective for the specific PKC isoform.

<b>Applications</b>
The present technology opens up an innovative therapeutic approach for the treatment of inflammatory diseases in which the identified compounds can serve as starting points for drug development. First experiments indicate relevance particularly for chronic obstructive pulmonary disease (COPD).

<b>Advantages</b>
• Innovative potent small molecules for selective PKCζ inhibition
• Allosteric mode of action increases selectivity
• Highly versatile scaffold for the independent optimization of four substituents
• Specific targeting may contribute to fewer side effects
• Potential treatment of diseases with high unmet medical need