title: Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists.
abstract: Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Tomoaki_Hasui@takeda.co.jp
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hasui
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Taiichi
authors.initials: T
authors.lastname: Ora
authors.forename: Norio
authors.initials: N
authors.lastname: Ohyabu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishigaki
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Imura
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Igata
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Motoyaji
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Habuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Midori
authors.initials: M
authors.lastname: Ono
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Siedem
authors.forename: Tony P
authors.initials: TP
authors.lastname: Tang
authors.forename: Cassandra
authors.initials: C
authors.lastname: Gauthier
authors.forename: Lisa A
authors.initials: LA
authors.lastname: De Meese
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukumoto
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D008862:Microsomes, Liver / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists; D008958:Models, Molecular; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C570543:6-(1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2H-1,4-benzoxazin-3(4H)-one; D000959:Antihypertensive Agents; D048588:Benzoxazines; D000451:Mineralocorticoid Receptor Antagonists; D011720:Pyrazoles