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

Autor: Rennie GR; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Barden TC; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Bernier SG; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Carvalho A; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Deming R; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Germano P; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Hudson C; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Im GJ; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Iyengar RR; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Jia L; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Jung J; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Kim E; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Lee TW; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Mermerian A; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Moore J; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Nakai T; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Perl NR; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Tobin J; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Zimmer DP; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States., Renhowe PA; Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States. Electronic address: prenhowe@gmail.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 May 15; Vol. 40, pp. 127886. Date of Electronic Publication: 2021 Mar 02.
DOI: 10.1016/j.bmcl.2021.127886
Abstrakt: 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.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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