Design, synthesis and SAR investigation of thienosultam derivatives as ADAMTS-5 (aggrecanase-2) inhibitors

A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity,...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.2111-2116
Main Authors: Atobe, Masakazu, Maekawara, Naomi, Kawanishi, Masashi, Suzuki, Hiroko, Tanaka, Eiichi, Miyoshi, Shiro
Format: Article
Language:English
Subjects:
ADAM Proteins - antagonists & inhibitors
ADAM Proteins - metabolism
ADAMTS-5
ADAMTS5 Protein
Aggrecanase-2
Animals
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Male
Molecular Structure
Osteoarthritis
Rats, Sprague-Dawley
S1′ pocket
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Thienosultam
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacology
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Summary:A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.01.120