Development of a prodrug of hydantoin based TACE inhibitor. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: Tong, Ling; Kim, Seong Heon; Chen, Lei; Kosinski, Aneta; Shankar, Bandarpalle B.; Girijavallabhan, Vinay; Yang, De-Yi; Yu, Wensheng; Zhou, Guowei; Shih, Neng-Yang; Chen, Shiying; Hu, Mengwei; Lundell, Daniel; Niu, Xiaoda; Umland, Shelby; Kozlowski, Joseph A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 16(2017)
• Page Start: 3704
• Page End: 3708
• Publication Date: 2017-08-15
• Subjects: TACE inhibitors -- Hydantoin -- Prodrug -- Anti-inflammatory agent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.07.007
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood ( h WBA). However, lead compound2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.