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

Bioorg Med Chem Lett. 2021 May 15:40:127886. doi: 10.1016/j.bmcl.2021.127886. Epub 2021 Mar 2.

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.

Keywords: CYR715; Nitric oxide; Soluble guanylate cyclase; sGC; sGC stimulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Carboxylic Acids / chemistry*
  • 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 / metabolism
  • Oxidative Stress / drug effects
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Soluble Guanylyl Cyclase / metabolism*
  • Structure-Activity Relationship
  • Vasodilator Agents / administration & dosage
  • Vasodilator Agents / chemistry*
  • Vasodilator Agents / pharmacokinetics

Substances

  • Carboxylic Acids
  • Glucuronides
  • Vasodilator Agents
  • Nitric Oxide
  • Soluble Guanylyl Cyclase