133038-44-5Relevant articles and documents
Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile
Walton, Mary C.,Yang, Yun-Fang,Hong, Xin,Houk,Overman, Larry E.
, p. 6166 - 6169 (2015)
Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.
Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis
Scanio, Marc J. C.,Searle, Xenia B.,Liu, Bo,Koenig, John R.,Altenbach, Robert,Gfesser, Gregory A.,Bogdan, Andrew,Greszler, Stephen,Zhao, Gang,Singh, Ashvani,Fan, Yihong,Swensen, Andrew M.,Vortherms, Timothy,Manelli, Arlene,Balut, Corina,Jia, Ying,Gao, Wenqing,Yong, Hong,Schrimpf, Michael,Tse, Chris,Kym, Philip,Wang, Xueqing
, p. 1543 - 1548 (2019)
Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.
General Asymmetric Synthesis of Densely Functionalized Pyrrolidines via Endo-Selective [3+2] Cycloaddition of β-Quaternary-Substituted Nitroalkenes and Azomethine Ylides
Buchman, Marek,Greszler, Stephen N.,Liu, Bo,Searle, Xenia B.,Voight, Eric A.,Zhao, Gang
, p. 7620 - 7632 (2020)
A scalable endo-selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azomethine ylides is reported using a P,N-type ferrocenyl ligand and [Cu(OTf)]2·C6H6. The robust method is tolerant of a wide range of functionalities, including rarely reported quaternary nitroalkene substitution and heteroaromatic and hindered ortho-substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.
Design, synthesis and biological evaluation of novel 2-(5-aryl-1H-imidazol-1-yl) derivatives as potential inhibitors of the HIV-1 Vpu and host BST-2 protein interaction
Bode, Moira L.,Coyanis, E. Mabel,Mosebi, Salerwe,Njengele, Zikhona,Rashamuse, Thompho J.,Sayed, Yasien
, (2020/02/13)
Novel ethyl 2-(5-aryl-1H-imidazol-1-yl)-acetates 17 and propionates 18, together with their acetic acid 19 and acetohydrazide 20 derivatives, were designed and synthesized using TosMIC chemistry. Biological evaluation of these newly synthesized scaffolds in the HIV-1 Vpu- Host BST-2 ELISA assay identified seven hits (17a, 17b, 17c, 17g, 18a, 20f and 20g) with greater than 50% inhibitory activity. These hits were validated in the HIV-1 Vpu- Host BST-2 AlphaScreen and six of the seven compounds were found to have comparable percentage inhibitory activities to those of the ELISA assay. Compounds 17b and 20g, with consistent percentage inhibitory activities across the two assays, had IC50 values of 11.6 ± 1.1 μM and 17.6 ± 0.9 μM in a dose response AlphaScreen assay. In a cell-based HIV-1 antiviral assay, compound 17b exhibited an EC50 = 6.3 ± 0.7 μM at non-toxic concentrations (CC50 = 184.5 ± 0.8 μM), whereas compound 20g displayed antiviral activity roughly equivalent to its toxicity (CC50 = 159.5 ± 0.9 μM). This data suggests that compound 17b, active in both cell-based and biochemical assays, provides a good starting point for the design of possible lead compounds for prevention of HIV-1 Vpu and host BST-2 protein binding in new anti-HIV therapeutics.
SUBSTITUTED PYRROLIDINES AND THEIR USE
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Paragraph 0394, (2019/10/30)
The invention discloses compounds of Formula (I) wherein R1, R2, R3, R3A, R4, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
Preparation of homoallylic amines via a three-component coupling process
Battilocchio, Claudio,Labes, Ricardo,Ley, Steven V.,Ou, Xiaoxu
supporting information, p. 6652 - 6654 (2018/09/29)
A three-component synthesis of homoallylic amines is described. The allylboronic species were generated in situ by homologation of vinyl boroxines with trimethylsilyldiazomethane, then followed by trapping of the allylboron intermediate with imines. Twenty-seven compounds were successfully prepared in moderate to high yields. Imines bearing various functional groups were tolerated, including aliphatic, aromatic and heteroaromatic substituents. Further elaboration of some of the homoallylic amines to form azeditines is also reported.
Substituted Pyrrolidines and Methods of Use
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Paragraph 2066; 2076; 2114, (2018/04/20)
The invention discloses compounds of Formula (I) wherein R1, R2, R2A, R3, R3A, R4, R4A, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
Substituted Pyrrolidines and Methods of Use
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Paragraph 1532; 1541, (2018/04/20)
The invention discloses compounds of Formula (I) wherein R1, R2, R2A, R3, R3A, R4, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
Macrocyclic compounds for suppressing replication of hepatitis C virus
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Page/Page column 38; 39, (2016/05/24)
A compound as represented by Formula (I) is provided, wherein groups are defined in the description. The compound is used as HCV protease inhibitor for treating HCV infection.
MACROCYCLIC COMPOUNDS FOR SUPPRESSING REPLICATION OF HEPATITIS C VIRUS
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Page/Page column, (2015/02/19)
A compound as represented by Formula (I) is provided, wherein groups are defined in the description. The compound is used as HCV protease inhibitor for treating HCV infection.
