1. Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists
- Author
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Tomoaki Hasui, Boyd Steven A, Shoji Fukumoto, Cassandra Gauthier, Satoshi Endo, Hideki Matsui, Tony Pisal Tang, Christopher Stephen Siedem, Sachiko Shiotani, Atsushi Mizukami, Kouhei Asano, Koji Fuji, Taiichi Ohra, Nobuhiro Nishigaki, Keiji Kusumoto, Jun Fujimoto, Takahiro Sugimoto, Midori Ono, Satoshi Sogabe, Masato Oosawa, Lisa A. De Meese, Norio Ohyabu, and Noriyuki Habuka
- Subjects
Male ,Models, Molecular ,Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Pyrazole ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Desoxycorticosterone Acetate ,Structure-Activity Relationship ,chemistry.chemical_compound ,Mineralocorticoid receptor ,Oral administration ,Chlorocebus aethiops ,Oxazines ,Drug Discovery ,medicine ,Animals ,Humans ,Rats, Wistar ,Receptor ,Molecular Biology ,Antihypertensive Agents ,Mineralocorticoid Receptor Antagonists ,chemistry.chemical_classification ,Aldosterone ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Androgen Antagonists ,Rats ,Steroid hormone ,Receptors, Mineralocorticoid ,chemistry ,COS Cells ,Hypertension ,Pyrazoles ,Molecular Medicine ,Azole ,Lead compound - 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.
- Published
- 2014