title: Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Yamashita_Tohru@takeda.co.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Kakegawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Miwa
authors.forename: Toru
authors.initials: T
authors.lastname: Yamano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Funata
authors.forename: Jyun-Ichi
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Tani
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Mol
authors.forename: Hua
authors.initials: H
authors.lastname: Zou
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Biching
authors.initials: B
authors.lastname: Sang
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukatsu
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D003460:Crystallization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013148:Spironolactone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D013148:Spironolactone; D000103:Acetyl-CoA Carboxylase