Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2010.12.104 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.
Br J Anaesth
October 2023
Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA; Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address:
Background: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain.
View Article and Find Full Text PDFSystematic evaluation of structure-property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride.
Bioorg Med Chem
May 2021
Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia; CONCERT-Translational Cancer Research Centre, NSW 2750, Australia.
Article Synopsis
- - The study explored new amiloride analogs with enhanced anticancer properties, identifying compounds that are up to 100 times more potent against a target associated with cancer, while avoiding diuretic side effects.
- - Researchers evaluated twelve of these analogs for various properties including solubility, stability, and how well they are absorbed in the body, comparing them with traditional amiloride.
- - Ultimately, two analogs (AA1-39 and AA1-41) were chosen for further research due to their effectiveness in mouse models of cancer metastasis.
6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease.
Bioorg Med Chem Lett
December 2019
School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia. Electronic address:
The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, K = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies.
View Article and Find Full Text PDFOptimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.
Bioorg Med Chem Lett
February 2011
Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK.
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!