We have located links that may give you full text access.
Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase.
European Journal of Medicinal Chemistry 2018 May 26
Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Ki app vs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app