2. Academic Validation
  3. Development of a prodrug of hydantoin based TACE inhibitor

Development of a prodrug of hydantoin based TACE inhibitor

  • Bioorg Med Chem Lett. 2017 Aug 15;27(16):3704-3708. doi: 10.1016/j.bmcl.2017.07.007.
Ling Tong 1,  Seong Heon Kim 2,  Lei Chen 2,  Aneta Kosinski 2,  Bandarpalle B Shankar 2,  Vinay Girijavallabhan 2,  De-Yi Yang 2,  Wensheng Yu 2,  Guowei Zhou 2,  Neng-Yang Shih 2,  Shiying Chen 3,  Mengwei Hu 4,  Daniel Lundell 5,  Xiaoda Niu 5,  Shelby Umland 5,  Joseph A Kozlowski 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: ling.tong@merck.com.
  • 2 Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 3 Department of PPDM, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 4 Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 5 Department of Immunology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
PMID: 28711352 DOI: 10.1016/j.bmcl.2017.07.007
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 (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

Keywords

Anti-inflammatory agent; Hydantoin; Prodrug; TACE inhibitors.

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