Journal of Medicinal Chemistry p. 1074 - 1090 (1987)
Update date:2022-08-03
Topics:
Graham, Donald W.
Ashton, Wallace T.
Barash, Louis
Brown, Jeannette E.
Brown, Ronald D.
et al.
The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract.A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo.Many of the compounds were prepared in one step from an α-keto acid and a primary amide.The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl.With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 μM and a range of pharmacokinetic properties.By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer.The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.
View MoreHangzhou Showland Technology Co., Ltd.
Contact:86-571-88920516
Address:ROOM2118,NO.553,WENSAN ROAD,HANGZHOU,CHINA
JIN TAN CHENG'EN CHEMICAL CO.,LTD.
Contact:86-519-82116250
Address:NO.102,village Dongfang,conomic development zone
Wuhan Chemwish Technology Co., Ltd
website:http://www.chemwish.com/
Contact:+86-27-67849912
Address:Room 1311, Unit 2, Block1, Innovation Road East Lake High-tech Development Zone Wuhan, Hubei,P.R. China
Contact:0512-63006287
Address:no.88.YISHENG Road,etdz-WUJIANG,SUZHOU,CHINA
Wuxi Innopal International Trade CO.,LTD
Contact:+86-510-80711901-8003
Address:Room 402,Building 5,Longze Garden,No.17,South huanjiu Road,Yixing City, Jiangsu,China
Doi:10.1021/jm900098v
(2009)Doi:10.1016/j.bmcl.2007.10.057
(2008)Doi:10.1021/jo00964a007
(1973)Doi:10.1007/BF00757660
()Doi:10.1016/j.apcata.2020.117536
(2020)Doi:10.1002/anie.200453956
(2004)