About
45
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497
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Introduction
I have received a Ph.D. degree in chemistry in 1991 from the Freie Universität Berlin under the supervision of Prof. Dr. J. Mulzer, developing a new methodology for the stereoselective synthesis of natural products via Hiyama-Reaction. Afterwards as a Research Associate at Roche, Nutley., NJ, USA, working with M. R. Uskokovic, we invented a new versatile method for the synthesis of vitamin D and steroid derivatives by application of a stereoselective Pauson-Khand-Reaction.
Additional affiliations
March 1999 - present
Endotherm GmbH
Position
- CEO
Description
- Executing a wide variety of external and internal research projects in medicinal, clinical and synthetic organic chemistry
October 1994 - September 1995
June 1993 - September 1994
Position
- PostDoc Position
Description
- Design, synthesis and biochemical evaluation of new 5reductase inhibitors as pharmacological compounds for the treatment of hormone mediated prostate cancer
Education
September 1982 - May 1991
Publications
Publications (45)
Pharma or biotech companies are looking to gain a significant added value to complemen~ strengthen or replace internal capabilities concerning capa city, costs, speed and technology. Even small start-up drug discovery companies often outsource their chemistry already from the beginning of their operations, because their investors force them to do s...
Optogenetic tools have become indispensable in neuroscience to stimulate or inhibit
excitable cells by light. Channelrhodopsin-2 (ChR2) variants have been established by
mutating the opsin backbone or by mining related algal genomes. As an alternative strategy,
we surveyed synthetic retinal analogues combined with microbial rhodopsins for functiona...
This book chapter provides an overview of versatile and efficient chemical syntheses of vitamin D derivatives by application of either linear or convergent synthesis approaches. Synthesis of the most relevant naturally-occurring vitamin D metabolites and their deuterated counterparts for use as calibration and reference standards in LC-MS/MS assays...
Increased sarcoplasmic reticulum (SR) Ca ²⁺ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca ²⁺ leak and improved survival in pressure overload (PO) and...
Sulfoximines have been largely disregarded in medicinal chemistry for a long time. However, recently, they have risen to the apparent level of stardom on the drug discovery scene. Considering the outstanding properties of sulfoximines, this versatile functional group has advanced to implementation in several drug discovery programs. Currently, this...
After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM...
Background/aim:
Simultaneous assessment of various vitamin D metabolites in human biofluids by liquid chromatography tandem mass spectrometry (LC-MS/MS) represents a new promising tool for the differential diagnosis of vitamin D-related diseases. Particularly, besides 25(OH)VD2/3, low-abundant medicinally relevant vitamin D metabolites, such as 24...
A novel approach to an A-ring synthon for Pd-catalyzed synthesis of 1α-hydroxylated vitamin D metabolites is described. Key step is an asymmetric glyoxylate ene reaction to access a highly diastereomerically pure α-hydroxy ester. Subsequent stereospecific transformation to an anti-1,3-diol and appropriate chemical modifications at both ends of the...
The secondary parallel hypercalcemic effects associated with the treatment of several hyperproliferative diseases with the natural hormone 1α,25‐dihydroxyvitamin D3 (calcitriol) and/or known active vitamin D metabolites and analogs, demand the development of efficient and rapid methods for the preparation of vitamin D receptor (VDR) ligands as new...
Vitamin D deficiency might cause a wide variety of human disorders. As a prerequisite for appropriate diagnosis and therapy, medicinally relevant vitamin D metabolites have to be assayed most accurately and with high specificity. It has been demonstrated, that vitamin D conjugates, linked via a hydroxyl group at C11, might be promising for the deve...
Vitamin D2 is a form of vitamin D derived from mushrooms and plants which is structurally modified in the body due to the action of several enzymes. The resulting metabolites represent important compounds with potential bioactive properties. However, they are poorly studied and their availability is mostly limited. In order to identify new enzymes...
Due to latest advancements in the development of LC-MS/MS based assays and their applications in clinical chemistry, low abundant vitamin D metabolites can be detected at low concentration with high specificity. Consequently, there is a growing need for their synthesis as stable isotopically labeled compounds to be used as calibration and reference...
In recent years the apparent impact of vitamin D deficiency on human health has gained increased awareness. Consequently, the development of appropriate assays to measure the status of medicinally most relevant vitamin D metabolites in human blood, serum or relevant tissue is continuously being improved. Particularly, assaying of 1α,25-dihydroxyvit...
Due to the widespread impact of Vitamin D on human health, the development of numerous assays to measure the status of Vitamin D and its metabolites are continuously being improved, either in order to prevent Vitamin D deficiency or to develop new therapeutic rationales. Over 50 natural metabolites of Vitamin D are known to date, although only very...
Due to the widespread impact of vitamin D on human
health, the development of numerous assays to measure the
status of vitamin D and its metabolites are continuously
being improved, either in order to prevent vitamin D
deficiency or to develop new therapeutic rationales. Over 50
natural metabolites of vitamin D are known to date,
although only very...
In recent years it has been recognized that vitamin D deficiency is associated with a wide range of diseases, including various types of cancers. Due to the enormous medical importance of vitamin D and its metabolites, their status in blood serum has to be accurately measured. Thus, the metabolites actually used as reference standards and also othe...
Vitamin D and its analogues are known for many distinguished roles in human physiology and pharmacology. Vitamin D is responsible for intestinal absorption of calcium and phosphate, and is critical to the process of bone mineralization. Vitamin D deficiency is associated with a variety of diseases, such as rickets, osteoporosis, psoriasis, leukemia...
Protein phosphatases (PP) are interesting drug targets. However, their ubiquitous presence and involvement in different, partially opposing signal pathways suggest that specificity may be achieved rather by targeting their interaction with subunits determining substrate specificity than the enzyme itself. An interesting subunit is phosphatase inhib...
Background:
L-type calcium channel (LTCC) and Na(+)/Ca(2+) exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrh...
Background
Inaccurate intracellular cycling (release and uptake) of Ca2+ through the relevant ion channels of the sarcoplasmatic reticulum (SR) is well recognized to be connected to arrhythmia trigger mechanisms. This is particularly true for an intracellular Ca2+ leak of the cardiac ryanodine receptor Ca2+ release channel RyR2 and/or a disturbed C...
The aim of this work was to perform a systematic study of the effect of nonionic detergents on the activity of the dengue virus NS2B-NS3 protease. To ensure a high activity of the protease, the assay procedures for the dengue virus and other flaviviral proteases published to date are performed in the presence of up to 35% glycerol, which does not r...
Feuerschutzmittel auf Maisstärkebasis Bonn (DMK) – Die Verwendungsmöglichkeiten von Maisstärke in der Industrie und der Erzeugung von Nahrungsmitteln sind ausgesprochen vielfältig. Neben der Herstellung von Papier, Wellpappe, Süß-oder Backwaren eignet sich Maisstärke auch als Brandschutz, berichtet das Deutsche Maiskomitee e.V. (DMK). Die Endotherm...
Die Saarbrücker Firma Endotherm hat ein Flammschutzmittel auf nanotechnologischer Basis entwickelt, das Materialien wie Holz, ,tilien, Papier, Pappe oder Stroh schwer \.. entflamm bar macht. Das Produkt namens "Eucam" ist von der Bauaufsicht zugelassen, ist auf seinem Untergrund völlig unsichtbar und lässt sich genauso einfach mit Pinsel oder Rolle...
Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. T...
In course of chromium(II) mediated additions of relatively complex allylic bromides to aldehydes (Hiyama–Nozaki allylation) radical intermediates have been observed. From these findings a new mechanism of the allylation is derived.
s -Das Thema Vorbeugender Brandschutz in The.atern, Rundfunkanstalten und anderen Versämmlungsstätten gewinnt zunehmend an Bedeutung. Dabei ist es oft nicht einfach, sich im 1J0rschriftendschungei zurechtzufinden und bei der täglichen Arbeit alle notwendigen Maßnahmen zu treffen, um einen Brandrisiko aus-zu sch Iiessen. Als Folge von Bränden in der...
Herstellung refraktiver Elemente aus Ormoceren mit hoher optischer Qualität Ziel des Projektes ist die Entwicklung neuartiger anorganisch-organischer Verbundpolymere zur Herstellung von optischen Materialien mit maßgeschneiderten optischen und mechanischen Eigenschaften. Radikalische Copolymerisation von vorhydrolysiertem (3 Methacryloxypropyl)-tri...
Several (carbamoylalkenyl)- and (carbamoylalkenyl)phenyloxy carboxylic acids (Table 1) and some of their ethyl esters (Table 2) were synthesized and evaluated in vitro as inhibitors of steroid 5α-reductase. Inhibitors of this enzyme may be useful in treating dihydrotestosterone-related diseases such as prostate cancer and benign prostatic hyperplas...
The chromium(II)-mediated addition (''Hiyama reaction'') of the chiral allylic bromides 13, 15, 19, 22, 24, and 27 to achiral and chiral aldehydes proceeds with high Felkin-Anh selectivity with respect to the stereocenter at C-gamma in the bromide (Table II). By double stereodifferentiation experiments (Tables III/IV) it was shown that the bromide...
The product (V), synthesized starting with a Hiyama addition of the chiral allyl bromide (I) to the aldehyde (II), is found to be identical with natural dihydrocanadensolide, a metabolite of Penicillium canadense.
Owing to its four chirality centers and the bicyclic para-conic acid lactone structure, dihydrocanadensolide 1, a metabolite of Penicillium canadense,['l is an attractive syn-thetic target molecule. The configuration first proposed for 1 was later r e v i ~ e d [ ~ > ~ ] but is still not unequivocally elucidated. CFCI,. the synthesis and isolation...
Questions
Question (1)
I have discovered a unique methodology towards the synthesis of Vitamin D derivatives and various steroids. I am now looking for a partner working in that field and interested in intlicensing of this patent
Projects
Projects (3)
A new research grant for an Eurostars-Eureka project has approved for Endotherm GmbH, starting this month. The consortium has the aim to develop a novel allosteric modulator to treat post-traumatic stress disorder (PTSD). The company has received a grant of 354 T€ for a duration of 3 years.
PTSD is a serious condition that can lead to intense fear and anxiety. However, current medication is unspecific, ineffective and has a vast number of side effects (sedation; abuse potential; sexual dysfunction). As a result, a majority of people with PTSD do not get effective treatment. DiSARM FEAR addresses this issue by selectively targeting mGluR7 with NAMs, thereby modulating brain circuitries involved in fear and anxiety, resulting in higher efficacy and significantly fewer side effects.
The consortium will deliver a novel clinical candidate for Post-Traumatic Stress Disorder (PTSD), by developing small-molecule negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 7 (mGluR7) to reduce fear memory reconsolidation. We will generate a lead and perform pharmacology, ADME/PK, non-GLP toxicity and efficacy studies in new PTSD models. After the project, DiSARM FEAR will complete preclinical development and enter clinical trials.
The company will discover and develop new molecular structures by chemical modifications.
The goal of the CystArrest project is to deliver a novel therapeutic for the treatment of Polycystic Kidney Disease (PKD). PKD is the most common inherited kidney disease, and one of the most common of all life-threatening inherited diseases. Kidney cysts grow throughout life in patients with PKD, causing symptoms including severe pain, cyst infections, bleeding and abdominal distention, and eventually resulting in kidney failure. PKD is responsible for up to 1/10 of all patients needing dialysis or transplantation, corresponding to approximately 50,000 people across Europe. 50% of PKD patients require renal replacement therapy by the age of 60, resulting in health care costs of >€1.5 billion/year across Europe. A drug to treat or even slow the progression of the disease and to improve life expectancy among patients is the top unmet need cited by nephrologists. With no effective treatment options, this world-wide health concern calls for urgent action.
This project will benefit from its unique approach to target the cell cycle, proliferation and apoptosis with a Roscovitine-derived CDK/CK1 inhibitor. The therapeutic potential for Roscovitine in treatment has already been recognized by academia and the biopharmaceutical industry particularly in treatment of cancer, but is a novel drug candidate for the treatment of PKD. The starting point of this project are a chemical derivative series of the CDK/CK1 inhibitor Roscovitine that were demonstrated to attenuate cyst growth in a unique 3D cell screening platform as model for PKD, enabling the recapitulation of the in vivo disease phenotype. By further characterization and optimization of these derivatives, this project will develop a first-in-class therapy, that targets an unexplored biological pathway in PKD with the first drug-like series of CDK inhibitors to enter clinical trials within two years after the end of the project.
The consortium aims to deliver a drug candidate, selected based on its efficacy to inhibit cyst formation, in vitro in a 3D cyst model and PKD biopsy material, and in vivo in PKD animal models. Throughout the project, further lead optimization, renal targeting and tolerance/toxicity and optimal pharmacological properties will be addressed before preparation for a clinical trial after this project.
Duration: 12/2018 - 11/2021
Budget (for Endotherm): 298 T€
The project has the aim to synthesize the most relevant naturally-occurring bioactive vitamin D metabolites and their deuterated counterparts for their use as calibration and reference standards in LC-MS/MS assays. By application of advanced mass spectrometric approaches these vitamin D metabolites are assayed in human biofluids aiming to correlate their distributions with various human diseases.
