Dataset Information

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

ABSTRACT: Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T_1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T_1/2 = 67 min) in RLM, with an IC₅₀ of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.

SUBMITTER: Huang MX

PROVIDER: S-EPMC9182104 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Huang Meng-Xing MX Chen Yan-Quan YQ Liu Run-Duo RD Huang Yue Y Zhang Chen C

Molecules (Basel, Switzerland) 20220526 11

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T<sub>1/2</sub>) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compound ...[more]

PMID: 35684390

Similar Datasets

Project description:BackgroundThere are two US Food and Drug Administration (FDA)-approved drugs, pirfenidone and nintedanib, for treatment of patients with idiopathic pulmonary fibrosis (IPF). However, neither of these drugs provide a cure. In addition, both are associated with several drug-related adverse events. Hence, the pursuit for newer IPF therapeutics continues. Recent studies show that joint analysis of systems-biology-level information with drug-disease connectivity are effective in discovery of biologically relevant candidate therapeutics.MethodsPublicly available gene expression signatures from patients with IPF were used to query a large-scale perturbagen signature library to discover compounds that can potentially reverse dysregulated gene expression in IPF. Two methods were used to calculate IPF-compound connectivity: gene expression-based connectivity and feature-based connectivity. Identified compounds were further prioritized if their shared mechanism(s) of action were IPF-related.ResultsWe found 77 compounds as potential candidate therapeutics for IPF. Of these, 39 compounds are either FDA-approved for other diseases or are currently in phase II/III clinical trials suggesting their repurposing potential for IPF. Among these compounds are multiple receptor kinase inhibitors (e.g. nintedanib, currently approved for IPF, and sunitinib), aurora kinase inhibitor (barasertib), epidermal growth factor receptor inhibitors (erlotinib, gefitinib), calcium channel blocker (verapamil), phosphodiesterase inhibitors (roflumilast, sildenafil), PPAR agonists (pioglitazone), histone deacetylase inhibitors (entinostat), and opioid receptor antagonists (nalbuphine). As a proof of concept, we performed in vitro validations with verapamil using lung fibroblasts from IPF and show its potential benefits in pulmonary fibrosis.ConclusionsAs about half of the candidates discovered in this study are either FDA-approved or are currently in clinical trials for other diseases, rapid translation of these compounds as potential IPF therapeutics is possible. Further, the integrative connectivity analysis framework in this study can be adapted in early phase drug discovery for other common and rare diseases with transcriptomic profiles.The reviews of this paper are available via the supplemental material section.

Dataset Information

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Publications

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets