Novel Amide Derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic Acids as Multifunctional TRPA1 Antagonists and PDE4/7 Inhibitors: A New Approach for the Treatment of Pain

Grażyna Chłoń-Rzepa, Marietta Ślusarczyk, Agnieszka Jankowska, Alicja Gawalska, Adam Bucki, Marcin Kołaczkowski, Artur Świerczek, Krzysztof Pociecha, Elżbieta Wyska, Małgorzata Zygmunt, Grzegorz Kazek, etc.

Eur J Med Chem. 2018 Oct 5;158:517-533.

PMID: 30245393

Abstract:

A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP433695364	BRL 50481		433695-36-4	Price
IAR4245724	PDE7A active rat			Price