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  • Toxicological and safety studies performed to complete the

    2020-07-30

    Toxicological and safety studies performed to complete the profile of LAS191589 showed that so far, it is a safe compound. No issues have been detected in any of the studies performed in terms of cytotoxicity, cardiovascular safety, central nervous system safety and genotoxicity. No relevant adverse effects have been observed in 1, 4, and 14days toxicological studies in different preclinical species. Although it is premature to postulate that a slowly dissociating CRTh2 antagonist with the potential to produce long lasting receptor blockade will be an advantage for ampar treatment, other compounds with similar characteristics exist in the market. A number of drugs have slow dissociation rate, including among others, angiotensin receptor antagonists like candesartan (dissociation half-life: 11.5h), muscarinic M3 receptor antagonists like tiotropium and aclidinium (dissociation half-life: 62h and 29h, respectively) or histamine H1R antagonist such as desloratadine (dissociation half-life: >6h), that contribute to their therapeutic effect and duration of action [41], [42], [43], [44].
    Conclusion The preclinical data reported in this study shows that LAS191859 is a potent and safe CRTh2 antagonist, with a long receptor residence time that provides a sustained in vivo efficacy. This property is reflected in the prolonged duration of action of LAS191859 in in vitro and in vivo functional models. The results presented here are the first to demonstrate that long receptor residence time in the CRTh2 receptor translates into a long-lasting efficacy in vivo and this efficacy is achieved in the absence of pharmacologically relevant systemic plasma levels.
    Acknowlegement
    CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), also known as DP, is a G-protein coupled receptor related to the -formyl peptide receptor (FPR) subfamily of chemoattractant receptors. Its endogenous ligand is prostaglandin D (PGD). PGD is the major cyclooxygenase product formed and secreted by activated mast cells during allergic reactions., , PGD also signals through prostanoid D (DP or DP) receptor. The DP receptor is primarily expressed on airway epithelium, smooth muscle and platelets, while CRTH2 is selectively expressed on Th2 cells, T cytotoxic type 2 (Tc2) cells, eosinophils, and basophils., , Stimulation of CRTH2 by PGD mediates multiple inflammatory responses, such as chemotaxis of eosinophils, basophils and Th2 cells, eosinophil activation and degranulation, cytokine production ampar from Th2 T cells, and leukotriene production by mast cells., , , , , , Therefore, blockade of CRTH2 is likely to be beneficial in the treatment of allergic diseases triggered by PGD. Several research groups, including ours, discovered that tetrahydroquinoline derivatives are potent CRTH2 antagonists., , , , , These compounds were of special interest to us, because to our knowledge, it was the only series of CRTH2 antagonists devoid of a carboxylic acid moiety. Here we report the discovery, optimization and structure activity relationship (SAR) of the tetrahydroquinoline derivatives.