Article ; Online: Identification and characterization of the new generation soluble guanylate cyclase stimulator BAY-747 designed for the treatment of resistant hypertension.
British journal of pharmacology
2023 Volume 180, Issue 19, Page(s) 2500–2513
Abstract: Background and purpose: First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC ... ...
| Abstract | Background and purpose: First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. Experimental approach: We report the high-throughput screening (HTS)-based discovery of a second generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY-747). The pharmacokinetic profile of BAY-747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. Key results: BAY-747 is a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY-747 caused a dose-related and long-lasting (>6 h) MAP decrease. Conclusion and implications: BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard-of-care therapy. |
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| MeSH term(s) | Rats ; Animals ; Dogs ; Soluble Guanylyl Cyclase ; Hypertension/drug therapy ; Hypertension, Pulmonary/drug therapy ; Heart Failure/drug therapy ; Vasodilator Agents/therapeutic use |
| Chemical Substances | Soluble Guanylyl Cyclase (EC 4.6.1.2) ; 2-(2-Chloro-4-(methylsulfonyl)-3-((2,2,2-trifluoroethoxy)methyl)benzoyl)-1,3-cyclohexanedione (BAY 747) ; Vasodilator Agents |
| Language | English |
| Publishing date | 2023-06-20 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 80081-8 |
| ISSN | 1476-5381 ; 0007-1188 |
| ISSN (online) | 1476-5381 |
| ISSN | 0007-1188 |
| DOI | 10.1111/bph.16142 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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