Discovery of a benzimidazole series of ADAMTS-5 (aggrecanase-2) inhibitors by scaffold hopping

We describe a medicinal chemistry approach to generate a series of benzimidazoles bearing thiazolidin-4-one using scaffold hopping from thiazole 1, our previously described thiazole. Our goal was to discover a potent and permeable small-molecule ADAMTS-5 inhibitor. The results suggest that small com...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2014-01, Vol.71, p.250-258
Main Authors: Sogame, Shinya, Suenaga, Yoshihito, Atobe, Masakazu, Kawanishi, Masashi, Tanaka, Eiichi, Miyoshi, Shiro
Format: Article
Language:English
Subjects:
ADAM Proteins - antagonists & inhibitors
ADAM Proteins - metabolism
ADAMTS-5
ADAMTS5 Protein
Benzimidazole
Benzimidazoles - chemistry
Benzimidazoles - pharmacokinetics
Benzimidazoles - pharmacology
Drug Design
Humans
Inhibitor
Osteoarthritis
Osteoarthritis - drug therapy
Permeability
Structure-Activity Relationship
Thiazolidin-4-one
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Summary:We describe a medicinal chemistry approach to generate a series of benzimidazoles bearing thiazolidin-4-one using scaffold hopping from thiazole 1, our previously described thiazole. Our goal was to discover a potent and permeable small-molecule ADAMTS-5 inhibitor. The results suggest that small compound 22 shows promise as a potent small-molecule ADAMTS-5 inhibitor with good permeability. [Display omitted] •We generated a series of benzimidazoles using scaffold hopping from thiazole.•We identified a potent ADAMTS-5 inhibitor using methyl-scanning.•We overcame poor permeability of thiazole derivative.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.10.075