Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947

Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry

“…For example, in 2020 Merck & Co. disclosed the discovery of MK-2947, a soluble guanylate cyclase stimulator for the treatment of hypertension. [14] A retrosynthetic analysis shows that the pyrrolopyrimidinone core could be accessed, for example, from compound E via condensation reactions (Scheme 2A). [15] With this in mind, we hypothesised that by changing the nature of the nucleophilic radical in our strategy -from an a-amino to a carbamoyl radicalwe could access a wide range of potential 5,5-substituted pyrrolopyrimidinones precursors with increased 3D character and Fsp 3 .…”

Electrochemical [4 + 1] Tandem sp3(C–H) Double Amination for the Direct Synthesis of 3-Acyl-Functionalized Imidazo[1,5-a]pyridines

“…Imidazo­[1,5- a ]­pyridines are featured fused N-heterocyclic compounds that have extensive applications in pharmaceutical chemistry for drug discovery . In recent years, a number of synthetic methods have been developed for the construction of these compounds, which greatly facilitates the research of the structure–activity relationship (SAR) for pharmaceutical chemists.…”

Riociguat therapy for pulmonary hypertension: a systematic review and meta-analysis

“…In the cardiovascular system, the combination of NO and sGC stimulates the enzyme to catalyze the conversion of guanosine 5'-triphosphate to cyclic guanosine-3',5'-monophosphate ( c G M P ) , w h i c h c o u l d l e a d t o s e v e r a l b e n e f i c i a l downstream physiological effects, including inhibition of vasodilation, platelet aggregation and smooth muscle cell proliferation (8). Thus, the NO-sGC-cGMP pathway has been shown to play an important role in the pathophysiologic process of PH (9). Riociguat is the first approved medication from the novel class of sGC stimulators and the only agent approved for treating both PAH and CTEPH (9)(10)(11).…”

“…Thus, the NO-sGC-cGMP pathway has been shown to play an important role in the pathophysiologic process of PH (9). Riociguat is the first approved medication from the novel class of sGC stimulators and the only agent approved for treating both PAH and CTEPH (9)(10)(11). It could stimulate sGC directly, independent of NO, and also sensitizes sGC to endogenous NO by stabilizing NO-sGC binding, leading to increased intracellular cGMP levels (9,12,13).…”

“…Riociguat is the first approved medication from the novel class of sGC stimulators and the only agent approved for treating both PAH and CTEPH (9)(10)(11). It could stimulate sGC directly, independent of NO, and also sensitizes sGC to endogenous NO by stabilizing NO-sGC binding, leading to increased intracellular cGMP levels (9,12,13). Thus, riociguat has antifibrotic, antiproliferative, and anti-inflammatory effects, in addition to vasodilatory properties.…”