2. Academic Validation
  3. Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

  • Bioorg Med Chem. 2014 Oct 1;22(19):5428-45. doi: 10.1016/j.bmc.2014.07.038.
Tomoaki Hasui 1,  Norio Ohyabu 2,  Taiichi Ohra 2,  Koji Fuji 2,  Takahiro Sugimoto 2,  Jun Fujimoto 2,  Kouhei Asano 2,  Masato Oosawa 2,  Sachiko Shiotani 2,  Nobuhiro Nishigaki 2,  Keiji Kusumoto 2,  Hideki Matsui 2,  Atsushi Mizukami 2,  Noriyuki Habuka 2,  Satoshi Sogabe 2,  Satoshi Endo 2,  Midori Ono 2,  Christopher S Siedem 3,  Tony P Tang 3,  Cassandra Gauthier 3,  Lisa A De Meese 3,  Steven A Boyd 3,  Shoji Fukumoto 2
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoaki.hasui@takeda.com.
  • 2 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
PMID: 25187277 DOI: 10.1016/j.bmc.2014.07.038
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.

Keywords

Aldosterone; MR; MR antagonists; Mineralocorticoid receptor; Nonsteroidal.

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