| Autor: |
Gordon Campbell, Anna Quattropani, Agnes Bombrun, Christophe Cleva, Marilène Gaudet, Gwenaelle Bouscary-Desforges, Marc Missotten, Stefano Crosignani, Hamina Daff, Kamel El Harkani, Tania Grippi-Vallotton, Nada Abla, Christèle Frémaux, Catherine Jorand-Lebrun, Zoë Johnson, Yves Humbert, Olivier Schott, Jean-François Arrighi, Charles G. Bradshaw, Mikaël Pâquet, Adeline Pretre, Pittet Pierre-Andre |
| Rok vydání: |
2011 |
| Předmět: |
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| Zdroj: |
ACS medicinal chemistry letters. 2(12) |
| ISSN: |
1948-5875 |
| Popis: |
Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack the carboxylic acid moiety. Compounds with high affinity (K i10 nM) for the receptor have been identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C191 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could represent an interesting alternative to current CRTH2 antagonists in development. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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