Wolfgang Wendler
Aventis Pharma
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Publication
Featured researches published by Wolfgang Wendler.
FEBS Letters | 2000
Werner Kramer; Heiner Glombik; Stephan Petry; Hubert Heuer; Hans-Ludwig Schäfer; Wolfgang Wendler; Daniel Corsiero; Frank Girbig; Claudia Weyland
To identify protein components of the intestinal cholesterol transporter, rabbit small intestinal brush border membrane vesicles were submitted to photoaffinity labeling using photoreactive derivatives of 2‐azetidinone cholesterol absorption inhibitors. An integral membrane protein of M r 145.3±7.5 kDa was specifically labeled in brush border membrane vesicles from rabbit jejunum and ileum. Its labeling was concentration‐dependently inhibited by the presence of cholesterol absorption inhibitors whereas bile acids, D‐glucose, fatty acids or cephalexin had no effect. The inhibitory potency of 2‐azetidinones to inhibit photolabeling of the 145 kDa protein correlated with their in vivo activity to inhibit intestinal cholesterol absorption. These results suggest that an integral membrane protein of M r 145 kDa is (a component of) the cholesterol absorption system in the brush border membrane of small intestinal enterocytes.
ChemMedChem | 2011
Stefanie Keil; Hans Matter; Karl Schönafinger; Maike Glien; Magali Mathieu; Jean-Pierre Marquette; Nadine Michot; Silke Haag‐Diergarten; Matthias Urmann; Wolfgang Wendler
Compounds that simultaneously activate the peroxisome proliferator‐activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high‐throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X‐ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF‐2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC50 values of 1.6 and 336 nM for PPARδ and γ, respectively. The X‐ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre‐diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.
Archive | 2002
Heiner Glombik; Eugen Falk; Wendelin Frick; Stefanie Keil; Hans-Ludwig Schäfer; Lothar Schwink; Wolfgang Wendler
Archive | 2001
Heiner Glombik; Eugen Falk; Wendelin Frick; Stefanie Keil; Hans-Ludwig Schaefer; Lothar Schwink; Wolfgang Wendler
Archive | 2005
Stefanie Keil; Hans-Ludwig Schaefer; Maike Glien; Stefan Guessregen; Wolfgang Wendler; Marion Esswein
Archive | 2006
Patrick Bernardelli; Stefanie Keil; Matthias Urmann; Hans Matter; Wolfgang Wendler; Maike Glien; Karen Chandross; Lan Lee; Corinne Terrier; Hervé Minoux
Acta Pharmacologica Sinica | 2012
Hans Ludwig Schäfer; Wolfgang Linz; Eugen Falk; Maike Glien; Heiner Glombik; Marcus Korn; Wolfgang Wendler; Andreas Herling; Hartmut Rütten
Archive | 2008
Karl Schoenafinger; Stefanie Keil; Matthias Urmann; Hans Matter; Maike Glien; Wolfgang Wendler
Archive | 2005
Stefanie Keil; Maike Glien; Hans-Ludwig Schaefer; Wolfgang Wendler; Patrick Bernardelli; Corinne Terrier; Baptiste Ronan
Archive | 2009
Stefanie Keil; Matthias Urmann; Wolfgang Wendler; Maike Glien; Hans Matter; Eugen Falk