18513-75-2Relevant academic research and scientific papers
Activity-Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists
Karageorgis, George,Dow, Mark,Aimon, Anthony,Warriner, Stuart,Nelson, Adam
, p. 13538 - 13544 (2015)
Activity-directed synthesis (ADS), a novel discovery approach in which bioactive molecules emerge in parallel with associated syntheses, was exploited to develop a weakly binding fragment into novel androgen receptor agonists. Harnessing promiscuous intermolecular reactions of carbenoid compounds enabled highly efficient exploration of chemical space. Four substrates were prepared, yet exploited in 326 reactions to explore diverse chemical space; guided by bioactivity alone, the products of just nine of the reactions were purified to reveal diverse novel agonists with up to 125-fold improved activity. Remarkably, one agonist stemmed from a novel enantioselective transformation; this is the first time that an asymmetric reaction has been discovered solely on the basis of the biological activity of the product. It was shown that ADS is a significant addition to the lead generation toolkit, enabling the efficient and rapid discovery of novel, yet synthetically accessible, bioactive chemotypes.
Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors
Liu, Yongfu,Wu, Jun,Zhou, Mingwei,Chen, Wenming,Li, Dongbo,Wang, Zhanguo,Hornsperger, Benoit,Aebi, Johannes D.,M?rki, Hans-Peter,Kuhn, Bernd,Wang, Lisha,Kuglstatter, Andreas,Benz, J?rg,Müller, Stephan,Hochstrasser, Remo,Ottaviani, Giorgio,Xin, Jian,Kirchner, Stephan,Mohr, Susanne,Verry, Philippe,Riboulet, William,Shen, Hong C.,Mayweg, Alexander V.,Amrein, Kurt,Tan, Xuefei
supporting information, p. 6876 - 6897 (2020/08/14)
Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.
Alkene synthesis by photocatalytic chemoenzymatically compatible dehydrodecarboxylation of carboxylic acids and biomass
Nguyen, Vu T.,Nguyen, Viet D.,Haug, Graham C.,Dang, Hang T.,Jin, Shengfei,Li, Zhiliang,Flores-Hansen, Carsten,Benavides, Brenda S.,Arman, Hadi D.,Larionov, Oleg V.
, p. 9485 - 9498 (2019/10/11)
Direct conversion of renewable biomass and bioderived chemicals to valuable synthetic intermediates for organic synthesis and materials science applications by means of mild and chemoselective catalytic methods has largely remained elusive. Development of artificial catalytic systems that are compatible with enzymatic reactions provides a synergistic solution to this enduring challenge by leveraging previously unachievable reactivity and selectivity modes. We report herein a dual catalytic dehydrodecarboxylation reaction that is enabled by a crossover of the photoinduced acridine-catalyzed O-H hydrogen atom transfer (HAT) and cobaloxime-catalyzed C-H-HAT processes. The reaction produces a variety of alkenes from readily available carboxylic acids. The reaction can be embedded in a scalable triple-catalytic cooperative chemoenzymatic lipase-acridine-cobaloxime process that allows for direct conversion of plant oils and biomass to long-chain terminal alkenes, precursors to bioderived polymers.
Isomerization of N-Allylamides and -imides to Aliphatic Enamides by Iron, Rhodium, and Ruthenium Complexes
Stille, J. K.,Becker Y.
, p. 2139 - 2145 (2007/10/02)
Substituted aliphatic N-propenylamides and -imides are readily sythesized from N-allylamides by double bond migration induced by rhodium or ruthenium hydrides.N-Propenylimides can be prepared from allylimides only in the presence of iron pentacarbonyl.
