Pharmazeutische Chemie


c-a-i-r biosciences GmbH is a privately owned company which focuses on the discovery and development of new drugs. The main therapeutic areas are inflammatory diseases like rheumatoide arthritis, chronic inflammatory bowel disease or psoriasis.
Target molecules are (1) protein kinases, (2) enzymes involved in the arachidonic acid cascade and (3) IMPDH, a key enzyme of the activation of immune cells.

Protein kinases of the MAP kinase pathway are promising targets for treatment of severe chronic inflammatory diseases. c-a-i-r biosciences GmbH owns intellectual property rights covering new small molecules with advantageous pharmacological characteristics. Ongoing research activities are funded by the German Ministry of Education and Research and by the lead investor Merckle GmbH, a member of the ratiopharm Group. The objective of the project is to identify 1-2 clinical candidates by the end of 2008. c-a-i-r biosciences GmbH is looking for development partners, licences or financial investors to commence non-clinical and clinical development of promising candidates.

A first clinical candidate, CBS-3595, was identified and based on its promising safety and efficacy profile, a first clinical trial was initiated. CBS-3595 is a dual inhibitor of p38 MAP kinase and phosphodiesterase-4 and a potential drug candidate for topical treatment of inflammatory diseased such as psoriasis or inflammatory bowel disease. Especially the combination with other topically administered drugs like 5-aminosalicylic acid appears to be a promising strategy.

Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the most frequently used drugs for symptomatic treatment of arthritis. Gastrointestinal and renal side effects are the most prominent disadvantages of this drug class. This led to the development of the so-called coxibs as the second generation NSAIDs with substantially improved gastrointestinal safety. Soon after entering the market, the drugs CELEBREX and VIOXX achieved block buster status.
However, in 2004, VIOXX was withdrawn from the market due to severe and life-threatening cardiovascular toxicity. Meanwhile, this side effect is considered as characteristic for this class of compounds. Dual inhibitors of cyclooxygenase and 5-lipoxygenase (LOX/COX) are gastro-protective, not cardiotoxic and have the potential to replace coxibs as NSAIDs. In addition, non-clinical studies suggest that drugs with this mechanism of action are beneficial for treatment of several forms of cancer. c-a-i-r biosciences is looking for a partner to inlicense and develop proprietary LOX/COX-inhibitors for treatment of osteoarthritis and in selected oncology indications.
As an extension of the LOX-COX research program, the potential of macrolide conjugates was evaluated. Macrolides (erythromycin and analogues) are preferably taken up by immune-competent cells, e.g. monocytes and macrophages. This characteristic is maintained in chemically modified, non-antibiotic macrolides and in non-antibiotic macrolides conjugated with a second, pharmacologically active drug. As such, macrolides are used to transport and enrich anti-inflammatory drugs to the site of action. The active drug is linked to the macrolide via a hydrolysable and thus, labile, ester bond. A spacer may be linked to optimize the rate of cleavage. IP rights of the technology platform was acquired and applied to proprietary dual inhibitors of Cyclooxygenase and 5-lipoxygenase. In a research project we applied this technology and prepared conjugates with two of our proprietary dual inhibitors of COX and 5-LOX. Pharmacological and preliminary toxicological characterization of these conjugates indicated an increased efficacy of macrolide-conjugates when compared to the LOX-COX-inhibitor alone.

In Japan, a nucleoside-prodrug is on the market for oral prevention of kidney transplant rejection and rheumatoid arthritis. The mechanism of actition is to inhibit the proliferation of immune cells by inhibition of the key enzyme inosine 5'-monophosphate dehydrogenase (IMPDH). After oral administration the drug enters systemic circulation and immune cells where the nucleoside is converted into the phosphorylated active IMPDH inhibitor. The objective of the planned project is to prepare masked proprietary nucleotides, which are orally bioavailable and pharmacologically active without the requirement of intracellular activation. The advantage of this strategy is to reduce the inter-individual variability of efficacy. Based on the valid target and the long-term experience with the nucleoside, the development of this drug is straightforward. The drug would compete with CellCept® which is currently marketed by Roche. In 2006, worldwide sales were 1.5 billion USD.