Novel anti-inflammatory compounds
Active

Dr. Zlatko Janeba, Dr. Viktor Kolman, Dr. Zdeněk Zídek, Dr. Helena Kaiserová-Mertlíková

Challenge

IN-VIVO MODEL OF ULCERATIVE COLITIS IN MICE

Example of substituted pyrimidines efficacy in DSS induced colitis in mice:

WQE-134 (in green) showed substantial mitigation of the inflammatory symptoms. WQE-134 in 10 mg/kg dose was superior to sulfasalazine and/or mesalazine in much higher doses. The efficacy was measured by the Disease Activity Index (DAI) combining the length of the colon, bleeding, stool consistency and loss of weight and by histology evaluation.

 

Ulcerative colitis or rheumatoid arthritis are diseases causing chronic inflammation (either in the colon or in joints), which (in the long term) stays behind tissue destruction resulting in pathological changes, pain and loss of tissue function. Due to unknown ethiology of both diseases, selective treatment is highly problematic. The huge rheumatoid arthritis drug market (18 B USD) is dominated by TNF-alpha inhibitor drugs (mainly anti-TNF-alpha antibodies) which are able to help patients but they are expensive and not easy to use. Moreover, in the case of ulcerative colitis, there is currently no cure available other than surgically removing affected colon tissue. Therefore, effective and non-toxic drugs belonging to a group of small molecules are highly needed either in ulcerative colitis or rheumatoid arthritis treatment. Novel pyrimidine derivatives were identified among promising anti-inflammatory drug candidates.

Technology

A library of novel pyrimidine derivatives has been prepared and tested for inhibition of prostaglandin E2 (PGE2) production using potentiated (LPS) mouse peritoneal macrophage model. The tested compounds inhibit the PGES1 synthase. However, the release of arachidonic acid from the membrane seems also to be influenced by some interaction of the tested molecules with the up-stream inflammation cascade. The concrete target in this up-stream cascade is not known and is a subject of further research.

Selected compounds were tested in animal models of acute or chronic colitis and rat rheumatoid arthritis model. Significant positive healing effects were observed after p.o. application using animal models of rheumatoid arthritis and ulcerative colitis (acute or chronic).

Commercial Opportunity

The technology is offered for co-development and licensing.

Development Status

Early preclinical stage, in vitro and in vivo testing. Optimization of the lead structure and validation of the target is proceeding.

Patent Situation

EP and US patent application with priority date in Feb 2011. Patent has been already granted in the US.

Co-developers

Institute of Experimental Medicine AS CR, v. v. i.