Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.
Administration, Oral
Animals
Carboxylic Acids
/ chemistry
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Glucuronides
/ administration & dosage
Humans
Hypertension, Pulmonary
/ drug therapy
Male
Metabolome
Models, Molecular
Nitric Oxide
/ metabolism
Oxidative Stress
/ drug effects
Protein Binding
Rats, Sprague-Dawley
Signal Transduction
Soluble Guanylyl Cyclase
/ metabolism
Structure-Activity Relationship
Vasodilator Agents
/ administration & dosage
CYR715
Nitric oxide
Soluble guanylate cyclase
sGC
sGC stimulator
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 05 2021
15 05 2021
Historique:
received:
10
09
2020
revised:
09
02
2021
accepted:
10
02
2021
pubmed:
5
3
2021
medline:
16
9
2021
entrez:
4
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33662540
pii: S0960-894X(21)00112-8
doi: 10.1016/j.bmcl.2021.127886
pii:
doi:
Substances chimiques
Carboxylic Acids
0
Glucuronides
0
Vasodilator Agents
0
Nitric Oxide
31C4KY9ESH
Soluble Guanylyl Cyclase
EC 4.6.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
127886Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.