title: Design, synthesis, and structure-activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists.
abstract: Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. tomoaki.hasui@takeda.com
authors: Tomoaki
authors: T
authors: Hasui
authors: Taiichi
authors: T
authors: Ohra
authors: Norio
authors: N
authors: Ohyabu
authors: Kouhei
authors: K
authors: Asano
authors: Hideki
authors: H
authors: Matsui
authors: Atsushi
authors: A
authors: Mizukami
authors: Noriyuki
authors: N
authors: Habuka
authors: Satoshi
authors: S
authors: Sogabe
authors: Satoshi
authors: S
authors: Endo
authors: Christopher S
authors: CS
authors: Siedem
authors: Tony P
authors: TP
authors: Tang
authors: Cassandra
authors: C
authors: Gauthier
authors: Lisa A
authors: LA
authors: De Meese
authors: Steven A
authors: SA
authors: Boyd
authors: Shoji
authors: S
authors: Fukumoto
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D048588:Benzoxazines / Q000737:chemistry*; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D015195:Drug Design; D020128:Inhibitory Concentration 50; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D048588:Benzoxazines; D000451:Mineralocorticoid Receptor Antagonists; D011758:Pyrroles; C464974:benzo(b)-2,3-dihydrofuran-2-one; C013231:pyrroline
keywords: Aldosterone; MR; Mineralocorticoid receptor; Nonsteroidal