Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors

Tohru Yamashita; Makoto Kamata; Satoshi Endo; Mitsuo Yamamoto; Keiko Kakegawa; Hiroyuki Watanabe; Katsuhiko Miwa; Toru Yamano; Masaaki Funata; Jyun-Ichi Sakamoto; Akiyoshi Tani; Clifford D Mol; Hua Zou; Douglas R Dougan; Biching Sang; Gyorgy Snell; Kohji Fukatsu

doi:10.1016/j.bmcl.2011.08.117

Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6314-8. doi: 10.1016/j.bmcl.2011.08.117. Epub 2011 Sep 6.

Authors

Tohru Yamashita¹, Makoto Kamata, Satoshi Endo, Mitsuo Yamamoto, Keiko Kakegawa, Hiroyuki Watanabe, Katsuhiko Miwa, Toru Yamano, Masaaki Funata, Jyun-Ichi Sakamoto, Akiyoshi Tani, Clifford D Mol, Hua Zou, Douglas R Dougan, Biching Sang, Gyorgy Snell, Kohji Fukatsu

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. [email protected]

PMID: 21944854
DOI: 10.1016/j.bmcl.2011.08.117

Abstract

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety.

MeSH terms

Acetyl-CoA Carboxylase / antagonists & inhibitors*
Crystallization
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Models, Molecular
Spironolactone / chemical synthesis*
Spironolactone / chemistry
Spironolactone / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Spironolactone
Acetyl-CoA Carboxylase