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

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

  • J Med Chem. 2021 Aug 12;64(15):11570-11596. doi: 10.1021/acs.jmedchem.1c00890.
Zhuming Zhang 1,  Avijit Ghosh 2,  Peter J Connolly 1,  Peter King 2,  Thomas Wilde 2,  Jianyao Wang 2,  Yawei Dong 3,  Xueliang Li 3,  Daohong Liao 3,  Hao Chen 3,  Gaochao Tian 4,  Javier Suarez 4,  William G Bonnette 4,  Vineet Pande 5,  Karen A Diloreto 2,  Yifan Shi 2,  Shefali Patel 2,  Beth Pietrak 4,  Lawrence Szewczuk 4,  Carlo Sensenhauser 2,  Shannon Dallas 2,  James P Edwards 1,  Kurtis E Bachman 6,  David C Evans 2
Affiliations

Affiliations

  • 1 Discovery Chemistry, Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 2 Drug Metabolism and Pharmacokinetics, Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 3 Chemistry, Pharmaron Beijing, Co. Ltd., No. 6, TaiHe Road, BDA Beijing 100176, P. R. China.
  • 4 Discovery Technology and Molecular Pharmacology, Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 5 Discovery Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 6 Oncology Discovery, Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
PMID: 34279934 DOI: 10.1021/acs.jmedchem.1c00890
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115866
    98.80%, COX抑制剂
    COX
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