title: A novel aldosterone synthase inhibitor ameliorates mortality in pressure-overload mice with heart failure.
abstract: It has been elucidated that mineralocorticoid receptor antagonists reduce mortality in patients with congestive heart failure and post-acute myocardial infarction. A direct inhibition of aldosterone synthase (CYP11B2) is also expected to have therapeutic benefits equal in quality to mineralocorticoid receptor antagonists in terms of reducing mineralocorticoid receptor signaling. Therefore, we have screened our chemical libraries and identified a novel and potent aldosterone synthase inhibitor, 2,2,2-trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-y}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol (compound 1), by lead optimization. Pharmacological properties of compound 1 were examined in in vitro cell-based assays and an in vivo mouse model of pressure-overload hypertrophy by transverse aortic constriction (TAC). Compound 1 showed potent CYP11B2 inhibition against human and mouse enzymes (IC50; 0.003μM and 0.096μM, respectively) in a cell-based assay. The oral administration of 0.06% compound 1 in the food mixture of a mouse TAC model significantly reduced the plasma aldosterone level and ameliorated mortality rate. This study is the first to demonstrate that a CYP11B2 inhibitor improved survival rates of heart failure induced by pressure-overload in mice. The treatment of 0.06% compound 1 did not elevate plasma potassium level in this model, although further evaluation of hyperkalemia is needed. These results suggest that compound 1 can be developed as a promising oral CYP11B2 inhibitor for pharmaceutical applications. Compound 1 could also be a useful compound for clarifying the role of aldosterone in cardiac hypertrophy.
authors.affiliation: End-Organ Disease Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan. Electronic address: furuzono.shinji.k5@daiichisankyo.co.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Furuzono
authors.affiliation: Biologics & Immuno-Oncology Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Meguro
authors.affiliation: Analytical & Quality Evaluation Research Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyauchi
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: End-Organ Disease Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Homma
authors.affiliation: Rare Disease & LCM Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Yoh-Ichi
authors.initials: YI
authors.lastname: Tagawa
authors.affiliation: Biologics & Immuno-Oncology Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.affiliation: Cell Therapy Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000401:mortality*; D006801:Humans; D051379:Mice; D011312:Pressure / Q000009:adverse effects*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D011743:Pyrimidines; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2
keywords: Aldosterone synthase; Heart failure; Transverse aortic constriction