22446-37-3Relevant articles and documents
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Levine,Eble,Fischbach
, p. 1930 (1948)
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Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid
Krogsgaard-Larsen, Niels,Delgar, Claudia G.,Koch, Karina,Brown, Patricia M. G. E.,M?ller, Charlotte,Han, Liwei,Huynh, Tri H. V.,Hansen, Stinne W.,Nielsen, Birgitte,Bowie, Derek,Pickering, Darryl S.,Kastrup, Jette Sandholm,Frydenvang, Karla,Bunch, Lennart
, p. 441 - 457 (2017)
Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach
Lorthiois, Edwige,Roache, James,Barnes-Seeman, David,Altmann, Eva,Hassiepen, Ulrich,Turner, Gordon,Duvadie, Rohit,Hornak, Viktor,Karki, Rajeshri G.,Schiering, Nikolaus,Weihofen, Wilhelm A.,Perruccio, Francesca,Calhoun, Amy,Fazal, Tanzina,Dedic, Darija,Durand, Corinne,Dussauge, Solene,Fettis, Kamal,Tritsch, Fabien,Dentel, Celine,Druet, Adelaide,Liu, Donglei,Kirman, Louise,Lachal, Julie,Namoto, Kenji,Bevan, Douglas,Mo, Rose,Monnet, Gabriela,Muller, Lionel,Zessis, Richard,Huang, Xueming,Lindsley, Loren,Currie, Treeve,Chiu, Yu-Hsin,Fridrich, Cary,Delgado, Peter,Wang, Shuangxi,Hollis-Symynkywicz, Micah,Berghausen, Joerg,Williams, Eric,Liu, Hong,Liang, Guiqing,Kim, Hyungchul,Hoffmann, Peter,Hein, Andreas,Ramage, Paul,D'arcy, Allan,Harlfinger, Stefanie,Renatus, Martin,Ruedisser, Simon,Feldman, David,Elliott, Jason,Sedrani, Richard,Maibaum, Juergen,Adams, Christopher M.
, p. 8088 - 8113 (2020)
The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1′ pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.
Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
supporting information, p. 2713 - 2718 (2021/06/25)
In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
