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Development of a prodrug of hydantoin based TACE inhibitor |
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| Authors: | Ling Tong Seong Heon Kim Lei Chen Aneta Kosinski Bandarpalle B Shankar Vinay Girijavallabhan De-Yi Yang Wensheng Yu Guowei Zhou Neng-Yang Shih Shiying Chen Mengwei Hu Daniel Lundell Xiaoda Niu Shelby Umland Joseph A Kozlowski |
| Institution: | 1. Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Department of PPDM, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;3. Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. Department of Immunology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA |
| 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: | TACE inhibitors Hydantoin Prodrug Anti-inflammatory agent |
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