Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator

[Display omitted] 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 t...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 40; p. 127886
Main 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.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-05-2021
Subjects:	Administration, Oral Animals Carboxylic Acids - chemistry CYR715 Dose-Response Relationship, Drug Drug Evaluation, Preclinical Glucuronides - administration & dosage Glucuronides - chemistry Glucuronides - pharmacokinetics Humans Hypertension, Pulmonary - drug therapy Male Metabolome Models, Molecular Nitric oxide Nitric Oxide - metabolism Oxidative Stress - drug effects Protein Binding Rats Rats, Sprague-Dawley sGC sGC stimulator Signal Transduction Soluble guanylate cyclase Soluble Guanylyl Cyclase - metabolism Structure-Activity Relationship Vasodilator Agents - administration & dosage Vasodilator Agents - chemistry Vasodilator Agents - pharmacokinetics DETA-NO SAR AG POCl3 HLM SNAr sGC AUC TEA RLM THF NaH sGC stimulator Nitric oxide Soluble guanylate cyclase IDT CYP MAP ODQ CYR715
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Summary:	[Display omitted] 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2021.127886