Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator. (15th May 2021)

• Record Type: Journal Article
• Authors: Rennie, Glen R.; Barden, Timothy C.; Bernier, Sylvie G.; Carvalho, Andrew; Deming, Renee; Germano, Peter; Hudson, Colleen; Im, G-Yoon J.; Iyengar, Rajesh R.; Jia, Lei; Jung, Joon; Kim, Elise; Lee, Thomas W.-H.; Mermerian, Ara; Moore, Joel; Nakai, Takashi; Perl, Nicholas R.; Tobin, Jenny; Zimmer, Daniel P.; Renhowe, Paul A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 40(2021)
• Publication Date: 2021-05-15
• Subjects: sGC soluble guanylate cyclase -- DETA-NO diethylenetriamine NONOate -- AUC area under the curve -- RLM rat liver microsome -- HLM human liver microsome -- MAP mean arterial pressure -- SAR structure–activity relationship -- TEA triethyl amine -- NaH sodium hydride -- THF tetrahydrofuran -- SNAr nucleophilic aromatic substitution -- POCl3 phosphorus(V) oxide chloride -- AG acyl glucuronide conjugate -- IDT idiosyncratic drug toxicity -- ODQ 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one -- CYP cytochrome P450 isoenzymes; Soluble guanylate cyclase -- sGC -- sGC stimulator -- Nitric oxide -- CYR715; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127886
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague–Dawley rats.