Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer.

Abstract

Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.

• Authors: Zhuming Zhang, Avijit Ghosh, Peter J Connolly, Peter King, Thomas Wilde, Jianyao Wang, Yawei Dong, Xueliang Li, Daohong Liao, Hao Chen, Gaochao Tian, Javier Suarez, William G Bonnette, Vineet Pande, Karen A Diloreto, Yifan Shi, Shefali Patel, Beth Pietrak, Lawrence Szewczuk, Carlo Sensenhauser, Shannon Dallas, James P Edwards, Kurtis E Bachman, David C Evans
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 15 Pg. 11570-11596 (08 12 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34279934 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase 2
• Celecoxib
• Etoricoxib

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Celecoxib (chemistry, metabolism, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (chemistry, metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Etoricoxib (chemistry, metabolism, pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Structure-Activity Relationship