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Published on: June 20, 2014
Biaryl substituted hydantoin compounds as TACE inhibitors
Wensheng Yu1, Ling Tong, Seong Heon Kim
1Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. wensheng.yu@merck.com
Bioorganic & Medicinal Chemistry Letters
|July 29, 2010
Summary
Further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors yielded potent compounds. These novel biaryl hydantoins exhibit sub-nanomolar inhibition and favorable pharmacokinetic properties.
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibitors
- Drug Discovery
Background:
- Tumor Necrosis Factor-alpha Convertase (TACE) is a key target in inflammatory diseases.
- Previous hydantoin-based inhibitors showed promise but required further optimization.
Purpose of the Study:
- To optimize hydantoin-based TACE inhibitors through structure-activity relationship (SAR) studies.
- To explore modifications in the non-prime region of the TACE active site.
Main Methods:
- Synthesis of a series of biaryl substituted hydantoin compounds.
- Evaluation of inhibitory activity (K(i)) against TACE.
- Assessment of pharmacokinetic (PK) properties in rats.
- Selectivity profiling against matrix metalloproteinases (MMPs).
Main Results:
- Optimized hydantoin compounds achieved sub-nanomolar inhibition constants (K(i)) for TACE.
- The novel compounds demonstrated good pharmacokinetic profiles in rat models.
- Excellent selectivity was observed against MMP-1, -2, -3, -7, -9, and -13.
Conclusions:
- Further optimization of hydantoin TACE inhibitors is feasible.
- Biaryl substituted hydantoins represent a promising class of TACE inhibitors.
- These compounds warrant further investigation for therapeutic potential in TACE-mediated conditions.
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