Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists

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Abstract

The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10 nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.

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Acknowledgment

We thank Maarten te Molder for the synthesis of several of the analogs.

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    Our initial pharmacological work to identify dihydropyrimidine (DHPM) scaffold as potent inhibitors of cholinesterases led us to design a new tricyclic building block [16]. Thus, synthesis of DHPM-based fused ring system (25) was planned through reaction of 1,3-indanedione (22) as a 1,3-dicarbonyl precursor in the Biginelli reaction [30]. The synthesized 25 was then reacted with intermediate 21 to synthesize target heterodimer 4c (see Scheme 4).

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Present address: Hasselt University, Agoralaanbuilding, 3590 Diepenbeek, Belgium.

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