The Experts below are selected from a list of 519 Experts worldwide ranked by ideXlab platform
G. Paul Savage - One of the best experts on this subject based on the ideXlab platform.
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Facial selectivity induced by N-aryl Atropisomerism in benzonitrile oxide cycloadditions with 4-methylene-2-oxazolidinones.
Organic & Biomolecular Chemistry, 2012Co-Authors: Sarah L. Harding, G. Paul SavageAbstract:N-Aryl 4-methylene-2-oxazolidinones, prepared via the corresponding O-propargyl carbamates, underwent nitrile oxide cycloaddition with benzonitrile oxide to give 5-spiro isoxazoline adducts with complete regioselectivity. Steric hindrance by Atropisomerism around the N-aryl bond induced facial selectivity in these cycloadditions.
Eddy Damen - One of the best experts on this subject based on the ideXlab platform.
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Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
Journal of Medicinal Chemistry, 2020Co-Authors: Jo Waaler, Sven T. Sowa, Albert Galera-prat, Ruben Gerardus George Leenders, Shoshy Alam Brinch, Max Lycke, Piotr Nieczypor, Sjoerd Aertssen, Sudarshan Murthy, Eddy DamenAbstract:Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous Atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
Rinaldo Poli - One of the best experts on this subject based on the ideXlab platform.
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synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals
Coordination Chemistry Reviews, 2016Co-Authors: Pauline Loxq, Eric Manoury, Rinaldo Poli, Eric Deydier, Agnes LabandeAbstract:Abstract Axially chiral biaryl structures are unique systems encountered in various synthetic compounds such as BINAP and BINOL, polymers, but also in natural products presenting a pharmaceutical interest such as Vancomycin, Steganacin or Korupensamine. The axial chirality of these products, so-called Atropisomerism, is induced by the restricted rotation around the aryl–aryl bond. This review will summarize the different strategies imagined by chemists to control such chirality, focusing on asymmetric catalytic processes with transition metals. Only transition metal complexes bearing chiral ligands will be considered and the core of this review will consist of the enantioselective coupling of two achiral substrates.
Pauline Loxq - One of the best experts on this subject based on the ideXlab platform.
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synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals
Coordination Chemistry Reviews, 2016Co-Authors: Pauline Loxq, Eric Manoury, Rinaldo Poli, Eric Deydier, Agnes LabandeAbstract:Abstract Axially chiral biaryl structures are unique systems encountered in various synthetic compounds such as BINAP and BINOL, polymers, but also in natural products presenting a pharmaceutical interest such as Vancomycin, Steganacin or Korupensamine. The axial chirality of these products, so-called Atropisomerism, is induced by the restricted rotation around the aryl–aryl bond. This review will summarize the different strategies imagined by chemists to control such chirality, focusing on asymmetric catalytic processes with transition metals. Only transition metal complexes bearing chiral ligands will be considered and the core of this review will consist of the enantioselective coupling of two achiral substrates.
Rebecca E Oconnor - One of the best experts on this subject based on the ideXlab platform.
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discovery and lead optimization of atropisomer d1 agonists with reduced desensitization
Journal of Medicinal Chemistry, 2018Co-Authors: Jennifer E Davoren, Deane M Nason, Jotham Wadsworth Coe, Keith Dlugolenski, Christopher John Helal, Anthony R Harris, Erik Alphie Lachapelle, Sidney Liang, Yue Liu, Rebecca E OconnorAbstract:The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic for chronic illness such as schizophrenia and Parkinson’s disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. An important structural feature of this series is the locked biaryl ring system resulting in Atropisomerism. Disclosed herein is a summary of our hit-to-lead efforts on this series of D1 activators culminating in the discovery of atropisomer 31 (PF-06256142), a potent and selective orthosteric agonist of the D1 receptor that has reduced receptor desensitization relative to dopamine and other catechol-containing agonists.