Licencing Opportunity:

This work represents a licensing opportunity.

Histamine H4-antagonist project The histamine H4 receptor The histamine H4 receptor (H4R) is a G-potein coupled receptor that has been discovered in 2001. It is the fourth member of the histaminergic receptor subfamily and has attracted much attention from both academia and industry. The H4R is mainly expressed in peripheral tissues and on cells of the immune system such as macrophages, mast cells and eosinophils. The H4R appears to be involved in a wide range of inflammatory processes involved with asthma, rheumatoid arthritis and inflammatory bowel disease as well as the mediation of itch. Literature reports several cases in which H4R antagonists have been used to succesfully modulate inflammatory processes in vivo. Molecular pharmacology At the VU University we design and synthesize new non-imidazole H4R lead compounds as candidates for clinical development. Our drug discovery efforts are guided by a strong expertise in the field of molecular biology and molecular pharmacology of GPCRs. We have developed several propietary cell lines that are being used for H4R binding and functional assays that give accurate and highly reproducible results. In addition to this, we have considerable expertise in emerging drug discovery opportunities such as receptor dimerisation, inverse agonism and allosteric modulation. Design and synthesis Our design and synthesis department has developed receptor homology models with excellent resolution and which have been validated by a wealth of experimental data. Next to our protein-based in silico screening approaches for hit finding, we also succesfully apply in silico pharmacophore design and subsequent pharmacophore searches using our propietary compound library. This library of over 15000 drug-like compounds has been the result of over 30 years of GPCR research and contains many unique compounds. We have broad experience in hit optimisation employing various organic synthestic techniques such as microwave assisted and parrallel chemistry. H4R non-imidazole ligands In the past years we have developed several non-imidazole H4R antagonists, although we have also found and published two selective H4R agonists, one of which contains an imidazole moiety. Currently we have several propietary nanomolar H4R antagonists. Two chemical series are in the lead optimisation stage and bind to the H4R in the low nanomolar range (pKi 8-9). H4R functional assays have shown these compounds to be inverse agonists with anti-inflammatory properties in-vivo. One of these series has been protected by two patents, the other series has not yet been protected. At present our group is interested in drug discovery collaborations or licensing oppportunities in the the area of H4 research. Key references 1. Lim et al, J. Pharmacol. Exp. Ther. 2005, 314:1310-21 2. de Esch et al, Trends Pharmacol. Sci. 2005, 26 :462-9 3. Thurmond et al, Nat.Rev.Drug Discov. 2008, 7:41-53 4. Smits et al, J. Med. Chem. 2008, Epub ahead of print Relevant patents: WO2008003702, others have been filed but not yet published. Contact details: R. A. Smits VU University Department of Medicinal Chemistry Faculty of Exact Sciences De Boelelaan 1083 1081 HV Amsterdam The Netherlands E-mail: rasmits@few.vu.nl

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