title: Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.
abstract: In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoaki.hasui@takeda.com.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hasui
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ohyabu
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Ohra
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fuji
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sugimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Asano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Oosawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Shiotani
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishigaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kusumoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizukami
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Habuka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Ono
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Siedem
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Tony P
authors.initials: TP
authors.lastname: Tang
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Gauthier
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: De Meese
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukumoto
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D064791:Desoxycorticosterone Acetate; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010078:Oxazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000596444:6-(5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl)-benzoxazin-3-one; D000726:Androgen Antagonists; D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D010078:Oxazines; D011720:Pyrazoles; D018161:Receptors, Mineralocorticoid; D064791:Desoxycorticosterone Acetate
keywords: Aldosterone; MR; MR antagonists; Mineralocorticoid receptor; Nonsteroidal