62673-31-8Relevant articles and documents
Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase
Abell, Lynn M.,Basso, Michael D.,Cantor, Glenn H.,Clark, Charles G.,Dilger, Andrew K.,Dongre, Ashok,Duclos, Franck,Duke, Gerald,Gao, Ji,Jusuf, Sutjano,Khan, Javed,Kick, Ellen K.,Kopcho, Lisa M.,Krishnakumar, Arathi,Locke, Gregory A.,Onorato, Joelle M.,Shaw, Scott A.,Spronk, Steven A.,Viet, Andrew,Vokits, Benjamin P.,Wexler, Ruth R.,Zhao, Lei
, (2020)
Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions
Menges-Flanagan, Gabriele,Deitmann, Eva,G?ssl, Lars,Hofmann, Christian,L?b, Patrick
, p. 427 - 433 (2021/01/09)
The continuous synthesis of organozinc reagents and their immediately following subsequent also continuous consumption in catalyzed and noncatalyzed coupling reactions were investigated. In the first step, a bed of Zn turnings at variable liquid throughputs and concentrations of organic halide solutions was used, and the formed Zn organometallics were analyzed for quality control. They were then directly pumped into a second step, namely, Reformatsky, Saytzeff, and Negishi coupling reactions. In the organozinc halides' formation, a novel process window was employed by using a large molar excess of Zn turnings and investigating mechanical as well as chemical Zn activation. Subsequent couplings of the freshly prepared Zn organometallics were done using examples of a Reformatsky, Saytzeff, and Negishi coupling reaction. For the Zn organometallics' formation, a laboratory-scale reactor setup previously built for Grignard reagent formation was evaluated including a Zn replenishing unit; the same reactor was also used in the metal-catalyzed subsequent step (Negishi coupling). The main objective of this work was to establish the scalable continuous formation of Zn organometallic reagents enabling fast and safe process optimization, analyze the reagents for their purity, and then immediately consume them in various follow-up steps, always only leaving a very small amount of reactive and sensitive organometallic reagent in the setup. It was found that full conversion of the employed halides could be achieved within a single passage through the reactor with organozinc yields of 82-92%, as well as being able to successfully perform subsequent non- and metal-catalyzed coupling steps with yields of up to 92%. A pilot-scale setup allowing a liquid throughput of up to 3-5 L/h has also been built and is ready to be tested with the synthesis as established here.
C(sp3)?C(sp3) Bond Formation via Electrochemical Alkoxylation and Subsequent Lewis Acid Promoted Reactions
López, Enol,van Melis, Carlo,Martín, Raúl,Petti, Alessia,de la Hoz, Antonio,Díaz-Ortíz, ángel,Dobbs, Adrian P.,Lam, Kevin,Alcázar, Jesús
supporting information, p. 4521 - 4525 (2021/08/06)
A two-step transition metal-free methodology for the C(sp3)?C(sp3) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF3 ? OEt2, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this methodology. Such an approach is especially relevant to drug discovery since it increases C(sp3)-functionalities rapidly within a molecular framework. As proof of concept, our methodology was applied to derivatization of peptides and an API. (Figure presented.).
