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Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines
Published on: January 3, 2018
Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates
J I Levin1, J M Chen, L M Laakso
1Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. levinji@wyeth.com
Bioorganic & Medicinal Chemistry Letters
|January 24, 2006
Summary
Researchers developed novel thiomorpholine sulfonamide hydroxamate TACE inhibitors. Compound 5h demonstrated potent activity and was selected as a clinical candidate for treating rheumatoid arthritis (RA).
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Immunology
Background:
- Tumor necrosis factor-alpha-converting enzyme (TACE) plays a crucial role in inflammatory diseases like rheumatoid arthritis (RA).
- Developing potent and orally active TACE inhibitors is a key therapeutic strategy for RA management.
Purpose of the Study:
- To synthesize and evaluate a novel series of thiomorpholine sulfonamide hydroxamate TACE inhibitors.
- To identify a clinical candidate with excellent in vitro and in vivo efficacy for RA treatment.
Main Methods:
- Synthesis of thiomorpholine sulfonamide hydroxamate derivatives with propargylic ether P1' groups.
- In vitro enzymatic and cellular assays to determine TACE inhibitory potency.
- In vivo studies using TNF-alpha production and collagen-induced arthritis models to assess oral activity.
Main Results:
- The synthesized compounds exhibited varying degrees of TACE inhibition.
- Compound 5h demonstrated excellent in vitro potency against isolated TACE and in cellular assays.
- Compound 5h showed significant oral activity in both TNF-alpha production and collagen-induced arthritis models.
Conclusions:
- Compound 5h, a thiomorpholine sulfonamide hydroxamate TACE inhibitor, possesses promising therapeutic potential for rheumatoid arthritis.
- The favorable in vitro and in vivo profile of compound 5h supports its advancement as a clinical candidate for RA treatment.
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