Crystal structure of the mineralocorticoid receptor ligand-binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS-3150)

FEBS Letters

article

Mizuki Takahashi¹  Osamu Ubukata²  Tsuyoshi Homma³  Yusuke Asoh⁴  Masatoshi Honzumi⁵  Noriyuki Hayashi⁶  Keiji Saito⁶  Hiroyuki Tsuruoka⁷  Kazumasa Aoki⁶  Hiroyuki Hanzawa¹ 

[1] Structure-Based Drug Design Group, Organic Synthesis Department, Ltd.;Protein Production Research Group, Biological Research Department, Ltd.;Global Project Management Department, Ltd.;IT Strategy Department, Ltd.;Process Technology Research Laboratories, Ltd.;Medicinal Chemistry Research Laboratories, Ltd.;Intellectual property department, Ltd.

关键词: antihypertensive drug;    esaxerenone;    hypertension;    mineralocorticoid receptor blocker;    non-steroidal structure;    nuclear receptor;   

DOI  :  10.1002/1873-3468.13746

来源: John Wiley & Sons Ltd.

【 摘 要 】

Activation of the mineralocorticoid receptor (MR) has long been considered a risk factor for cardiovascular diseases. It has been reported that the novel MR blocker esaxerenone shows high potency and selectivity for MR in vitro as well as great antihypertensive and renoprotective effects in salt-sensitive hypertensive rats. Here, we determined the cocrystal structure of the MR ligand-binding domain (MR-LBD) with esaxerenone and found that esaxerenone binds to MR-LBD in a unique manner with large side-chain rearrangements, distinct from those of previously published MR antagonists. This structure also displays an antagonist form that has not been observed for MR previously. Such a unique binding mode of esaxerenone provides great insight into the novelty, potency, and selectivity of this novel antihypertensive drug.

【 授权许可】

Unknown