title: Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
abstract: The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: arai.kiyoshi.ch@daiichisankyo.co.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Arai
authors.affiliation: Biological Research 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: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ubukata
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiyoyuki
authors.initials: H
authors.lastname: Tsuruoka
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Sada
mesh_terms: D000284:Administration, Oral; D000315:Adrenalectomy; D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077545:Eplerenone; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011188:Potassium / Q000652:urine; D011485:Protein Binding; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000652:urine; D013148:Spironolactone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D064804:Urological Agents / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; C561839:NR3C2 protein, human; D011758:Pyrroles; D018161:Receptors, Mineralocorticoid; D013450:Sulfones; D064804:Urological Agents; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D064791:Desoxycorticosterone Acetate; D012964:Sodium; C000607547:esaxerenone; D011188:Potassium
keywords: Aldosterone; CS-3150; Mineralocorticoid receptor antagonist; Urinary Na(+)/K(+) ratio