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

Shinya Sogame; Yoshihito Suenaga; Masakazu Atobe; Masashi Kawanishi; Eiichi Tanaka; Shiro Miyoshi

doi:10.1016/j.ejmech.2013.10.075

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

Eur J Med Chem. 2014 Jan:71:250-8. doi: 10.1016/j.ejmech.2013.10.075. Epub 2013 Nov 15.

Authors

Shinya Sogame¹, Yoshihito Suenaga¹, Masakazu Atobe², Masashi Kawanishi¹, Eiichi Tanaka¹, Shiro Miyoshi¹

Affiliations

¹ Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
² Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. Electronic address: atobe.mb@om.asahi-kasei.co.jp.

PMID: 24316668
DOI: 10.1016/j.ejmech.2013.10.075

Abstract

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.

Keywords: ADAMTS-5; Benzimidazole; Inhibitor; Osteoarthritis; Thiazolidin-4-one.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM Proteins / metabolism
ADAMTS5 Protein
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
Drug Design
Humans
Osteoarthritis / drug therapy
Permeability
Structure-Activity Relationship

Substances

Benzimidazoles
benzimidazole
ADAM Proteins
ADAMTS5 Protein
ADAMTS5 protein, human