Tetomilast

Drugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored.

In the last decades, the better understanding of inflammatory bowel diseases (IBD) pathogenesis has contributed to the identification of new therapeutic targets that can be modulated to induce and maintain disease remission. Monoclonal antibodies against tumor necrosis factor, interleukin (IL)-12/IL-23p40, and the integrin α4β7 and inhibitors of Janus kinase molecules are valid compounds to limit the function of molecules implicated in the control of IBD-related inflammation. However, not all patients respond to treatment with such drugs, some of them lose response over time and others develop serious side effects, such as infections or malignancies, which lead to the discontinuation of the therapy. Thus, an intensive research is ongoing with the goal to identify new targets and develop novel therapeutic options. In this context, restoration of TGF-β activity and inhibition of phosphodiesterase 4 (PD4) represent two relevant strategies. TGF-β is an immunesuppressive cytokine, whose activity is severely impaired in IBD due to the abundance of the intracellular inhibitor Smad7. Knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β signalling and dampens effector immune responses in pre-clinical studies and initial clinical trials in Crohn's disease patients, even though a recent phase 3 trial was discontinued due to an apparent inefficacy. PD4 inhibition determines the increase of intracellular levels of cyclic adenosine monophosphate, a mechanism that decreases pro-inflammatory cytokine production. A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD.