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
  • 1. Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: [email protected].
  • 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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