Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure

被引：173

作者：

Follmann, Markus ^{[1
]}

Ackerstaff, Jens ^{[1
]}

Redlich, Gorden ^{[1
]}

Wunder, Frank ^{[1
]}

Lang, Dieter ^{[1
]}

Kern, Armin ^{[1
]}

Fey, Peter ^{[1
]}

Griebenow, Nils ^{[1
]}

Kroh, Walter ^{[1
]}

Becker-Pelster, Eva-Maria ^{[1
]}

Kretschmer, Axel ^{[1
]}

Geiss, Volker ^{[1
]}

Li, Volkhart ^{[1
]}

Straub, Alexander ^{[1
]}

Mittendorf, Joachim ^{[1
]}

Jautelat, Rolf ^{[1
]}

Schirok, Hartmut ^{[1
]}

Schlemmer, Karl-Heinz ^{[1
]}

Lustig, Klemens ^{[1
]}

Gerisch, Michael ^{[1
]}

Knorr, Andreas ^{[1
]}

Tine, Hanna ^{[1
]}

Mondritzki, Thomas ^{[1
]}

Truebel, Hubert ^{[1
]}

Sandner, Peter ^{[1
]}

Stasch, Johannes-Peter ^{[1
]}

机构：

[1] Bayer AG, Drug Discovery, Aprather Weg 18a, D-42113 Wuppertal, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 12期

关键词：

PULMONARY ARTERIAL-HYPERTENSION; NITRIC-OXIDE; DRUG DISCOVERY; RIOCIGUAT; NO; PHARMACOKINETICS; ACTIVATORS; DYSFUNCTION; EXPRESSION; MODULATORS;

D O I：

10.1021/acs.jmedchem.7b00449

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.

引用

页码：5146 / 5161

页数：16

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