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https://repository.monashhealth.org/monashhealthjspui/handle/1/29340| Title: | Substituted 1-methyl-4-phenylpyrrolidin-2-ones - Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors. | Authors: | Zheng Z.;Thompson P.E.;Shortt J. ;Scanlon M.J.;Mountford S.J.;Johnstone R.W.;Hilton-Proctor J.P.;Jennings I.G.;Ilyichova O. | Monash Health Department(s): | Haematology | Institution: | (Hilton-Proctor, Ilyichova, Zheng, Jennings, Mountford, Scanlon, Thompson) Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia (Johnstone) Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, Australia (Johnstone) The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia (Shortt) Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, 246 Clayton Road, Clayton, Victoria, Australia (Shortt) Monash Haematology, Monash Health, 246 Clayton Road, Clayton, Victoria, Australia | Issue Date: | 16-Mar-2020 | Copyright year: | 2020 | Publisher: | Elsevier Masson SAS (62 rue Camille Desmoulins, Issy les Moulineaux Cedex 92442, France) | Place of publication: | France | Publication information: | European Journal of Medicinal Chemistry. 191 (no pagination), 2020. Article Number: 112120. Date of Publication: 1 April 2020. | Journal: | European Journal of Medicinal Chemistry | Abstract: | N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.Copyright © 2020 Elsevier Masson SAS | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/j.ejmech.2020.112120 | PubMed URL: | 32120339 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32120339] | ISSN: | 0223-5234 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/29340 | Type: | Article | Subjects: | gw 2286/an [Drug Analysis] gw 2286/dv [Drug Development] gw 2286 pyrrolidine derivative/an [Drug Analysis] pyrrolidine derivative/dv [Drug Development] pyrrolidine derivative unindexed drug 1 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] piperidine 3 carboxylic acid/an [Drug Analysis] 1 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] piperidine 3 carboxylic acid/dv [Drug Development] 1 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] piperidine 3 carboxylic acid 1 methyl 4 [4 ((4 phenylpiperidin 1 yl)sulfonyl)phenyl]pyrrolidin 2 one/an [Drug Analysis] 1 methyl 4 [4 ((4 phenylpiperidin 1 yl)sulfonyl)phenyl]pyrrolidin 2 one/dv [Drug Development] 1 methyl 4 [4 ((4 phenylpiperidin 1 yl)sulfonyl)phenyl]pyrrolidin 2 one 1 methyl 4 [4 (morpholinosulfonyl)phenyl]pyrrolidin 2 one/an [Drug Analysis] 1 methyl 4 [4 (morpholinosulfonyl)phenyl]pyrrolidin 2 one/dv [Drug Development] 1 methyl 4 [4 (morpholinosulfonyl)phenyl]pyrrolidin 2 one 1 methyl 4 [4 (piperidin 1 ylsulfonyl)phenyl]pyrrolidin 2 one/an [Drug Analysis] 1 methyl 4 [4 (piperidin 1 ylsulfonyl)phenyl]pyrrolidin 2 one/dv [Drug Development] 1 methyl 4 [4 (piperidin 1 ylsulfonyl)phenyl]pyrrolidin 2 one 1 methyl 4 phenylpyrrolidin 2 one/an [Drug Analysis] 1 methyl 4 phenylpyrrolidin 2 one/dv [Drug Development] 1 methyl 4 phenylpyrrolidin 2 one 3 (benzo[b]thiophen 3 yl) n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] 3 (benzo[b]thiophen 3 yl) n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] 3 (benzo[b]thiophen 3 yl) n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide 3 bromo n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] 3 bromo n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] 3 bromo n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide 4 (1 methyl 5 oxopyrrolidin 3 yl) n propylbenzenesulfonamide/an [Drug Analysis] 4 (1 methyl 5 oxopyrrolidin 3 yl) n propylbenzenesulfonamide/dv [Drug Development] 4 (1 methyl 5 oxopyrrolidin 3 yl) n propylbenzenesulfonamide 4 (2 bromophenyl) 1 methylpyrrolidin 2 one/an [Drug Analysis] 4 (2 bromophenyl) 1 methylpyrrolidin 2 one/dv [Drug Development] 4 (2 bromophenyl) 1 methylpyrrolidin 2 one 4 ([1,1' biphenyl] 2 yl) 1 methylpyrrolidin 2 one/an [Drug Analysis] 4 ([1,1' biphenyl] 2 yl) 1 methylpyrrolidin 2 one/dv [Drug Development] 4 ([1,1' biphenyl] 2 yl) 1 methylpyrrolidin 2 one 4 ([1,1' biphenyl] 4 yl) 1 methylpyrrolidin 2 one/an [Drug Analysis] 4 ([1,1' biphenyl] 4 yl) 1 methylpyrrolidin 2 one/dv [Drug Development] 4 ([1,1' biphenyl] 4 yl) 1 methylpyrrolidin 2 one 4 [4 ((3,4 dihydroquinolin 1(2h) yl)sulfonyl)phenyl] 1 methylpyrrolidin 2 one/an [Drug Analysis] 4 [4 ((3,4 dihydroquinolin 1(2h) yl)sulfonyl)phenyl] 1 methylpyrrolidin 2 one/dv [Drug Development] 4 [4 ((3,4 dihydroquinolin 1(2h) yl)sulfonyl)phenyl] 1 methylpyrrolidin 2 one 4 phenylpyrrolidin 2 one/an [Drug Analysis] 4 phenylpyrrolidin 2 one/dv [Drug Development] 4 phenylpyrrolidin 2 one 4' (dimethylamino) n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/an [Drug Analysis] 4' (dimethylamino) n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/dv [Drug Development] 4' (dimethylamino) n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide 8 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] 8 azabicyclo[3.2.1]octan 3 one/an [Drug Analysis] 8 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] 8 azabicyclo[3.2.1]octan 3 one/dv [Drug Development] 8 [(4 (1 methyl 5 oxopyrrolidin 3 yl)phenyl)sulfonyl] 8 azabicyclo[3.2.1]octan 3 one methyl 4 nitro 3 phenylbutanoate/an [Drug Analysis] methyl 4 nitro 3 phenylbutanoate/dv [Drug Development] methyl 4 nitro 3 phenylbutanoate n (adamantan 1 yl) 4 (1 methyl 5 oxopyrrolidin 3 yl) benzenesulfonamide/an [Drug Analysis] n (adamantan 1 yl) 4 (1 methyl 5 oxopyrrolidin 3 yl) benzenesulfonamide/dv [Drug Development] n (adamantan 1 yl) 4 (1 methyl 5 oxopyrrolidin 3 yl) benzenesulfonamide n [3 (1h imidazol 1 yl)propyl] 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] n [3 (1h imidazol 1 yl)propyl] 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] n [3 (1h imidazol 1 yl)propyl] 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide n benzyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] n benzyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] n benzyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide n ethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] n ethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] n ethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide n isopropyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] n isopropyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] n isopropyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide n,n diethyl 3' ,4' dimethoxy 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/an [Drug Analysis] n,n diethyl 3' ,4' dimethoxy 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/dv [Drug Development] n,n diethyl 3' ,4' dimethoxy 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 (3 phenylpropyl)benzenesulfonamide/an [Drug Analysis] n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 (3 phenylpropyl)benzenesulfonamide/dv [Drug Development] n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 (3 phenylpropyl)benzenesulfonamide n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 phenethylbenzenesulfonamide/an [Drug Analysis] n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 phenethylbenzenesulfonamide/dv [Drug Development] n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl) 3 phenethylbenzenesulfonamide n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/dv [Drug Development] n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/an [Drug Analysis] n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide/dv [Drug Development] n,n diethyl 6 (1 methyl 5 oxopyrrolidin 3 yl) [1,1' biphenyl] 3 sulfonamide n,n diethyl 4 (1 methyl 5 oxopyrrolidin 3 yl)benzenesulfonamide/an [Drug Analysis] bromination chiral chromatography crystal structure diastereoisomer drug design drug synthesis electrophilicity electrospray mass spectrometry fluorescence resonance energy transfer hydrogen bond hydrogenation Michael addition proton nuclear magnetic resonance reversed phase high performance liquid chromatography substitution reaction Suzuki reaction X ray crystallography bromodomain inhibitor/an [Drug Analysis] bromodomain inhibitor/dv [Drug Development] bromodomain inhibitor |
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