1000339-10-5Relevant articles and documents
Highly Potent 17β-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy
Siebenbuerger, Lorenz,Hernandez-Olmos, Victor,Abdelsamie, Ahmed S.,Frotscher, Martin,Van Koppen, Chris J.,Marchais-Oberwinkler, Sandrine,Scheuer, Claudia,Laschke, Matthias W.,Menger, Michael D.,Boerger, Carsten,Hartmann, Rolf W.
, p. 10724 - 10738 (2018)
Intracellular elevation of E2 levels in bone by inhibition of 17β hydroxysteroid dehydrogenase type 2 (17β-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17β-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development.
Inhibitors of 17Beta-Hydroxysteroid Dehydrogenases Type 1 and Type 2
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Paragraph 0303, (2016/12/12)
Provided herein are non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 and type 2 (17β-HSD1 and 17β-HSD2) inhibitors, their production and use, especially for the treatment and for prophylaxis of hormone-related diseases.
TUBULIN BINDING AGENTS
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, (2015/02/18)
The invention provides combretastatin A-4 like compounds that are modified to have enhanced tubulin binding activity and in some embodiments the ability to promote accumulation in the vasculature undergoing angiogenesis (homing activity). The compounds are based on the combretastatin A-4 skeletal structure having a tubulin-binding pharmacophore comprising two fused rings (A and B rings) in which the B ring is substituted with (a) an aromatic ring structure (C ring) and (b) a second substituent/functional group that comes off the B ring. The aromatic ring structure is typically a six membered ring phenolic or aniline structure, or may also be a fused ring structure such as a substituted or unsubstituted naphthalene. The second substituent on the B ring may for example be a substituent which has been found to provide enhanced tubulin binding activity (for example a carbonyl group), or may be a substituent that facilitates functionalisation of the B ring (for example an hydroxyl or amine group), or it may be a binding agent for a target that is preferentially expressed on vasculature undergoing angiogenesis, and not expressed on quiescent vasculature.
Highly selective phosphatidylinositol 4-kinase IIIβ inhibitors and structural insight into their mode of action
Mejdrová, Ivana,Chalupská, Dominika,K?gler, Martin,?ála, Michal,Pla?ková, Pavla,Baumlová, Adriana,H?ebabecky, Hubert,Procházková, Eli?ka,Dejmek, Milan,Guillon, Rémi,Strunin, Dmytro,Weber, Jan,Lee, Gary,Birkus, Gabriel,Mertlíková-Kaiserová, Helena,Boura, Evzen,Nencka, Radim
, p. 3767 - 3793 (2015/05/27)
Phosphatidylinositol 4-kinase IIIβ is a cellular lipid kinase pivotal to pathogenesis of various RNA viruses. These viruses hijack the enzyme in order to modify the structure of intracellular membranes and use them for the construction of functional repli
