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Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC 50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG 35-55 -induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT 1A /5-HT 7 receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT 1A /5-HT 7 receptor antagonist (5-HT 1A K i  = 8 nM, K b  = 0.04 nM; 5-HT 7 K i  = 451 nM, K b  = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC 50  = 80.4 μM; PDE7A IC 50  = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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 IC 50 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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC 50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)